Her3 ligands and uses thereof

ABSTRACT

Described herein, inter alia, are compositions of HER3 ligands and methods for treating diseases using the same.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/213,455, filed Sep. 2, 2015, which is incorporated herein byreference in its entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant no. R01GM109176, awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII FILE

The Sequence Listing written in file 48536-572001WO_ST25.TXT, createdAug. 30, 2016, 26,077 bytes, machine format IBM-PC, MS-Windows operatingsystem, is hereby incorporated by reference.

BACKGROUND

Pseudokinases are members of the large protein kinase family which donot exhibit substantial enzymatic activity. However, they do participatein signal transduction through orchestration of protein-proteininteractions with other active enzymes. HER3 in particular binds to HER2which is an active kinase. There is a need in the art for efficient andeffective blockers of HER3 function.

Disclosed herein are solutions to these and other problems in the art.

BRIEF SUMMARY

Provided herein, inter alma, are ligands for HER3, and methods of usingthe same.

In an aspect is provided a compound having the formula:

Ring A is aryl or heteroaryl. Ring B is aryl or heteroaryl. W¹ is N orC(R⁶). R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, —OCH₂X¹, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R¹ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² is independently a halogen, —CX² ₃, —CHX²₂, —CH₂X², —CN, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹²,—NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹², —C(O)R¹³,—C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX² ₃, —OCHX² ₂, —OCH₂X², substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R² substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁴ is independently a hydrogen,halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴ ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁵ is independently a hydrogen,halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁶ is independently a hydrogen,halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,and R¹⁴ are independently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂,—CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; R¹¹ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. L¹ is abond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—,—NHC(O)NH—, —S—, substituted or unsubstituted alkylene or substituted orunsubstituted heteroalkylene. L⁴ is a bond or a divalent linker. L⁵ is abond or a divalent linker. z1 and z2 are independently an integer from 0to 7. m1, m2, v1, and v2 are independently 1 or 2. n1 and n2 areindependently an integer from 0 to 4. X¹, X², X⁴, X⁵, X⁶, and X^(A) areindependently —Cl, —Br, —I, or —F.

In an aspect is provided a pharmaceutical composition including acompound described herein or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In an aspect is provided a method of treating a disease associated withHER3 activity in a patient in need of such treatment, the methodincluding administering a therapeutically effective amount of a compounddescribed herein, or a pharmaceutically acceptable salt thereof.

In an aspect is provided a method of treating a disease associated withEGFR activity, HER2 activity, HER4 activity, c-MET activity, PI3Kactivity, MEK activity, MAPK activity, RAF activity, BRAF activity, AKTactivity, RAS activity, KRAS activity, heregulin activity, or neuregulinactivity in a patient in need of such treatment, the method includingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt thereof.

In an aspect is provided a method of treating cancer in a patient inneed of such treatment, the method including administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt thereof.

In an aspect is provided a method of inhibiting HER3 activity, themethod including contacting HER3 with an effective amount of a compounddescribed herein, or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Bosutinib potently binds to HER3. FIG. 1 depicts ribbon diagramsshowing binding of bosutinib to X-ray crystallographic structure of HER3in two orientations differing by approximately 90°. Structure ofbosutinib depicted below ribbon diagrams. See Littlefield et al., Chem.Biol. 20:453 (2014).

FIG. 2. FIG. 2 depicts temperature dependence of unfolding (percentunfolding) for DMSO (circles), bosutinib (squares) 179D (triangles tipup), and 183 (triangles tip down). FIG. 2 also depicts structures ofbosutinib, TAK-185, Lapatinib, CP-724.714, Neratinib, 179D, and 183.

FIG. 3. FIG. 3 depicts a region of ribbon diagram showing 179D bindingin the back pocket in a Type 1 manner to EGFR. This depicts thatbuilding off of the terminal rings meta or para position may create atype 2 inhibitor.

FIG. 4. FIG. 4 demonstrates confirmation of 50A binding to HER3 TKD.Y-axis: percent unfolded protein; x-axis: temperature. Legend: DMSO(circles), 179D (squares), 50A (triangles). Structures of 50A and 179Dare provided. Observed is particularly tight binding of 50A to the HER3TKD.

FIGS. 5A-5B. In vitro kinase assays with 50A, FIG. 5A: In vitro Srckinase assay (30-min). Legend: bosutinib (circles), 50A (squares). IC₅₀(bosutinib)=3.3 nM. IC₅₀ (50A)=3.3 nM. Y-axis: percent (%) activity vs.DMSO (control); x-axis: log [compound]. FIG. 5B: In vitro HER2 kinaseassay (15-min). Legend: lapatinib (circles); 50A (triangles). Axes: asin FIG. 5A.

FIGS. 6A-6B. FIG. 6A depicts a cartoon structure of the interaction ofHER2 and HER3 at the membrane. FIG. 6B depicts results of treatment for1-hr in CHL-1 cells for (in order top to bottom): pHER2 (Y1139), HER2,pHER3 (Y1289), HER3, pAkt (T308), Akt, p-ERK, ERK, and COX IV. Assayconditions (left to right) at the indicated concentrations: DMSO, LAP,bosutinib, 179D and 50A. Chemical structures of bosutinib, 179D and 50Aare provided below the data. It is observed that Ambit profiling showsthat bosutinib binds tightly to MEK1, 2 and 5.

FIG. 7. Extended type II motif allows quinazolines to bind HER3. FIG. 7depicts percent unfolding as a function of temperature in the HER3 TKDThermofluor assay. Legend: DMSO (small squares), 50A (triangles tip up),73 (triangles tip down), 74A (diamonds), 74B (circles), 75A (largersquares), 75B (open triangle tip up). Chemical structures of 74A, 75A,73 74B, 75B and 50A are provided below the graph.

FIG. 8. FIG. 8 depicts binding of compound 73 in EGFR. Structure of cmpd73 is provided below ribbon diagram of expanded region of binding of 73in EGFR.

FIGS. 9A-9B. Depicted are chemical structures of compounds, which weredesigned to assess the potential of introducing biological activity intoa HER3 binder.

DETAILED DESCRIPTION A. DEFINITIONS

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchednon-cyclic carbon chain (or carbon), or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propenyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—). An alkyl moietymay be an alkenyl moiety. An alkyl moiety may be an alkenyl moiety. Analkyl moiety may be fully saturated.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from art alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched non-cyclicchain, or combinations thereof, including at least one carbon atom andat least one heteroatom (e.g., selected from the group consisting of O,N, P, Si, and S), and wherein the nitrogen and sulfur atoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) (e.g., O, N, P, S, and Si) may be placedat any interior position of the heteroalkyl group or at the position atwhich the alkyl group is attached to the remainder of the molecule.Examples include, but are not limited to: —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g.,O, N, S, Si, or P). A heteroalkyl moiety may include two optionallydifferent heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include three optionally different heteroatoms (e.g., O, N, S, Si,or P). A heteroalkyl moiety may include four optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefive optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include up to 8 optionally different heteroatoms(e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,3-hydroxy-cyclobut-3-enyl-1,2, dione, 1H-1,2,4-triazolyl-5(4H)-one,4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include,but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means a divalent radical derived from a cycloalkyl andheterocycloalkyl, respectively. A heterocycloalkyl moiety may includeone ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moietymay include two optionally different ring heteroatoms (e.g., O, N, S,Si, or P). A heterocycloalkyl moiety may include three optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include four optionally different ring heteroatoms (e.g., O,N, S, Si, or P). A heterocycloalkyl moiety may include five optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include up to 8 optionally different ring heteroatoms (e.g.,O, N, S, Si, or P).

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. Non-limiting examples of aryl and heteroarylgroups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl,indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl,pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl,quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl,benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl,pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl,furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl,benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl,diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl,or quinolyl. The examples above may be substituted or unsubstituted anddivalent radicals of each heteroaryl example above are non-limitingexamples of heteroarylene. A heteroaryl moiety may include one ringheteroatom (e.g., O, N, or S). A heteroaryl moiety may include twooptionally different ring heteroatoms (e.g., O, N, or S). A heteroarylmoiety may include three optionally different ring heteroatoms (e.g., O,N, or S). A heteroaryl moiety may include four optionally different ringheteroatoms (e.g., O, N, or S). A heteroaryl moiety may include fiveoptionally different ring heteroatoms (e.g., O, N, or S). An aryl moietymay have a single ring. An aryl moiety may have two optionally differentrings. An aryl moiety may have three optionally different rings. An arylmoiety may have four optionally different rings. A heteroaryl moiety mayhave one ring. A heteroaryl moiety may have two optionally differentrings. A heteroaryl moiety may have three optionally different rings. Aheteroaryl moiety may have four optionally different rings. A heteroarylmoiety may have five optionally different rings.

A fused ring heterocycloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl”,“heterocycloalkyl”, “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)N R′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, in a number ranging from zeroto (2m′+1), where m′ is the total number of carbon atoms in suchradical. R, R′, R″, R′″, and R″″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted heteroaryl, substituted orunsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.When a compound of the invention includes more than one R group, forexample, each of the R groups is independently selected as are each R′,R″, R′″, and R″″ group when more than one of these groups is present.When R′ and R″ are attached to the same nitrogen atom, they can becombined with the nitrogen atom to form a 4-, 5-, 6-, or 7-memberedring. For example, —NR′R″ includes, but is not limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and aryl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC (O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the totalnumber of open valences on the aromatic ring system; and where R′, R″,R′″, and R″″ are preferably independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″, and R″″ groupswhen more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,        —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,        —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,        unsubstituted aryl, unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,            —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₂,            —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo, halogen, —CF₃, —CN, —OH,                —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,                —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,                —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl.

A “size-limited substituent” or “ size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present invention containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present invention. Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as(R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomersare encompassed within the scope of the present invention. The compoundsof the present invention do not include those which are known in art tobe too unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,certain methods herein treat diseases associated with HER3 activity.Certain methods described herein may treat diseases associated with HER3activity (e.g., cancer) by inhibiting HER3 activity. For example,certain methods herein treat cancer. For example certain methods hereintreat cancer by decreasing a symptom of cancer. Symptoms of cancer wouldbe known or may be determined by a person of ordinary skill in the art.The term “treating” and conjugations thereof, include prevention of aninjury, pathology, condition, or disease. In embodiments, treating doesnot include preventing.

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reduceprotein function, reduce one or more symptoms of a disease orcondition). An example of an “effective amount” is an amount sufficientto contribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug or prodrugis an amount of a drug or prodrug that, when administered to a subject,will have the intended prophylactic effect, e.g., preventing or delayingthe onset (or reoccurrence) of an injury, disease, pathology orcondition, or reducing the likelihood of the onset (or reoccurrence) ofan injury, disease, pathology, or condition, or their symptoms. The fullprophylactic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a prophylactically effective amount may be administered in one ormore administrations. The exact amounts will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art. Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g.cancer) means that the disease is caused by (in whole or in part), or asymptom of the disease is caused by (in whole or in part) the substanceor substance activity or function. As used herein, what is described asbeing associated with a disease, if a causative agent, could be a targetfor treatment of the disease. For example, a disease associated withHER3 activity may be treated with an agent (e.g. compound as describedherein) effective for decreasing the level of HER3 activity.

“Control” or “control experiment” or “standard control” is used inaccordance with its plain ordinary meaning and refers to an experimentin which the subjects or reagents of the experiment are treated as in aparallel experiment except for omission of a procedure, reagent, orvariable of the experiment. In some instances, the control is used as astandard of comparison in evaluating experimental effects.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, that the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme. In some embodiments contacting includes allowing a compounddescribed herein to interact with a protein (e.g., HER3) or enzyme.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor (e.g. antagonist)interaction means negatively affecting (e.g. decreasing) the level ofactivity or function of the protein relative to the level of activity orfunction of the protein in the absence of the inhibitor. In someembodiments inhibition refers to reduction of a disease or symptoms ofdisease. Thus, inhibition may include, at least in part, partially ortotally blocking stimulation, decreasing, preventing, or delayingactivation, or inactivating, desensitizing, or down-regulating signaltransduction or enzymatic activity or the amount of a protein.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator (e.g. agonist) interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein relative to the activity or function of the protein in theabsence of the activator (e.g. compound described herein). Thus,activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.Activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule. Inembodiments, a modulator is an anti-cancer agent. In embodiments, amodulator is a HER3 antagonist. In embodiments, a modulator is a HER3agonist.

“Anti-cancer agent” or “anti-cancer drug” is used in accordance with itsplain ordinary meaning and refers to a composition (e.g. compound, drug,antagonist, inhibitor, modulator) having antineoplastic properties orthe ability to inhibit the growth or proliferation of cells. In someembodiments, an anti-cancer agent is a chemotherapeutic. In someembodiments, an anti-cancer agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcancer. Examples of anti-cancer agents include, but are not limited to,anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK(e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040,PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973,ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733,PD318088, AS703026, BAY 869766), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),ethylenimine and methylmelamines (e.g., hexamethylmelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomustine, semustine, streptozocin), triazenes (decarbazine)),anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine,fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog(e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel,docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.),antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin,epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin,etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin,carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea(e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide),epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin,doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors ofmitogen-activated protein kinase signaling (e.g. U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan),5-aza-2′-deoxycytidine, doxorubicin, vincristine, etoposide,gemcitabine, imatinib (Gleevec®) geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), bortezomib,trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogen,antiestrogen; antisense oligonucleotides; apoptosis gene modulators;apoptosis regulators; arginine deaminase; BCR/ABL antagonists; betalactam derivatives; bFGF inhibitor; bicalutamide; camptothecinderivatives; casein kinase inhibitors (ICOS); clomifene analogues;cytarabine dacliximab; dexamethasone; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;finasteride; fludarabine; fluorodaunorunicin hydrochloride; gadoliniumtexaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; letrozole; leukemia inhibiting factor;leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; mismatched double stranded RNA; monoclonalantibody; mycobacterial cell wall extract; nitric oxide modulators;oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogenactivator inhibitor; platinum complex; platinum compounds; prednisone;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; ribozymes; signal transductioninhibitors; signal transduction modulators; single chain antigen-bindingprotein; stem cell inhibitor; stem-cell division inhibitors; stromelysininhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;telomerase inhibitors; thyroid stimulating hormone; translationinhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists;steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,gonadotropin-releasing hormone agonists (GnRH) such as goserelin orleuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, pyrrolo benzodiazepines (e.g. tomaymycin),carboplatin, CC-1065 and CC-1065 analogs including amino-CBIs, nitrogenmustards (such as chlorambucil and melphalan), dolastatin and dolastatinanalogs (including auristatins: eg. monomethyl auristatin E),anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.),duocarmycins and duocarmycin analogs, enediynes (such asneocarzinostatin and calicheamicins), leptomycin derivatives,maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate,mitomycin C, taxoids, vinca alkaloids (such as vinblastine andvincristine), epothilones (e.g. epothilone B), camptothecin and itsclinical analogs topotecan and irinotecan, or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

“Patient” or “subject in need thereof” or “subject” refers to a livingorganism suffering from or prone to a disease or condition that can betreated by administration of a compound or pharmaceutical composition orby a method, as provided herein. Non-limiting examples include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In some embodiments, a patient ishuman. In some embodiments, a subject is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is a disease having the symptom of cellhyperproliferation. In some embodiments, the disease is a disease havingthe symptom of an aberrant level of HER3 activity. In some embodiments,the disease is a cancer. In some further instances, “cancer” refers tohuman cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas,leukemias, etc., including solid and lymphoid cancers, kidney, breast,lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, headand neck, skin, uterine, testicular, glioma, esophagus, and livercancer, including hepatocarcinoma, lymphoma, including B-acutelymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, SmallCell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (includingAML, ALL, and CML), or multiple myeloma. In embodiments, the disease isbrain cancer. In embodiments, the disease is neuroblastoma. Inembodiments, the disease is glioblastoma.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound or method provided herein include cancer of theprostate, thyroid, endocrine system, brain, breast, cervix, colon, head& neck, liver, kidney, lung, non-small cell lung, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma,colorectal cancer, pancreatic cancer. Additional examples may include,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroll, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity, aberrant refers to activity that isgreater or less than a normal control or the average of normalnon-diseased control samples. Aberrant activity may refer to an amountof activity that results in a disease, wherein returning the aberrantactivity to a normal or non-disease-associated amount (e.g. byadministering a compound or using a method as described herein), resultsin reduction of the disease or one or more disease symptoms.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same or have a specifiedpercentage of amino acid residues or nucleotides that are the same(i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or higher identity over a specified region whencompared and aligned for maximum correspondence over a comparison windowor designated region) as measured using a BLAST or BLAST 2.0 sequencecomparison algorithms with default parameters described below, or bymanual alignment and visual inspection (see, e.g., NCBI web site or thelike). Such sequences are then said to be “substantially identical.”This definition also refers to, or may be applied to, the compliment ofa test sequence. The definition also includes sequences that havedeletions and/or additions, as well as those that have substitutions. Asdescribed below, the preferred algorithms can account for gaps and thelike. Preferably, identity exists over a region that is at least about10 amino acids or 20 nucleotides in length, or more preferably over aregion that is 10-50 amino acids or 20-50 nucleotides in length. As usedherein, percent (%) amino acid sequence identity is defined as thepercentage of amino acids in a candidate sequence that are identical tothe amino acids in a reference sequence, after aligning the sequencesand introducing gaps, if necessary, to achieve the maximum percentsequence identity. Alignment for purposes of determining percentsequence identity can be achieved in various ways that are within theskill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR)software. Appropriate parameters for measuring alignment, including anyalgorithms needed to achieve maximal alignment over the full-length ofthe sequences being compared can be determined by known methods.

For sequence comparisons, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Preferably,default program parameters can be used, or alternative parameters can bedesignated. The sequence comparison algorithm then calculates thepercent sequence identities for the test sequences relative to thereference sequence, based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 10 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well-known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homologyalignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970),by the search for similarity method of Pearson & Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444 (1988), by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,Wis.), or by manual alignment and visual inspection (see, e.g., CurrentProtocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

Twenty amino acids are commonly found in proteins. Those amino acids canbe grouped into nine classes or groups based on the chemical propertiesof their side chains. Substitution of one amino acid residue for anotherwithin the same class or group is referred to herein as a “conservative”substitution. Conservative amino acid substitutions can frequently bemade in a protein without significantly altering the conformation orfunction of the protein. Substitution of one amino acid residue foranother from a different class or group is referred to herein as a“non-conservative” substitution. In contrast, non-conservative aminoacid substitutions tend to modify conformation and function of aprotein.

Example of Amino Acid Classification

Small/Aliphatic residues: Gly, Ala, Val, Leu, Ile Cyclic Imino Acid: ProHydroxyl-containing Residues: Ser, Thr Acidic Residues: Asp, Glu AmideResidues: Asn, Gln Basic Residues: Lys, Arg Imidazole Residue: HisAromatic Residues: Phe, Tyr, Trp Sulfur-containing Residues: Met, Cys

In some embodiments, the conservative amino acid substitution comprisessubstituting any of glycine (G), alanine (A), isoleucine (I), valine(V), and leucine (L) for any other of these aliphatic amino acids;serine (S) for threonine (T) and vice versa; aspartic acid (D) forglutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) andvice versa; lysine (K) for arginine (R) and vice versa; phenylalanine(F), tyrosine (Y) and tryptophan (W) for any other of these aromaticamino acids; and methionine (M) for cysteine (C) and vice versa. Othersubstitutions can also be considered conservative, depending on theenvironment of the particular amino acid and its role in thethree-dimensional structure of the protein. For example, glycine (G) andalanine (A) can frequently be interchangeable, as can alanine (A) andvaline (V). Methionine (M), which is relatively hydrophobic, canfrequently be interchanged with leucine and isoleucine, and sometimeswith valine. Lysine (K) and arginine (R) are frequently interchangeablein locations in which the significant feature of the amino acid residueis its charge and the differing pKs of these two amino acid residues arenot significant. Still other changes can be considered “conservative” inparticular environments (see, e.g., BIOCHEMISTRY at pp. 13-15, 2nd ed.Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat'lAcad. Sci. USA (1992) 89:10915-10919; Lei et al., J. Biol. Chem. (1995)270(20):11882-11886).

“Polypeptide,” “peptide,” and “protein” are used herein interchangeablyand mean any peptide-linked chain of amino acids, regardless of lengthor post-translational modification. As noted below, the polypeptidesdescribed herein can be, e.g., wild-type proteins, biologically-activefragments of the wild-type proteins, or variants of the wild-typeproteins or fragments. Variants, in accordance with the disclosure, cancontain amino acid substitutions, deletions, or insertions. Thesubstitutions can be conservative or non-conservative.

Following expression, the proteins can be isolated. The tern “purified”or “isolated” as applied to any of the proteins described herein refersto a polypeptide that has been separated or purified from components(e.g., proteins or other naturally-occurring biological or organicmolecules) which naturally accompany it, e.g., other proteins, lipids,and nucleic acid in a cell expressing the proteins. Typically, apolypeptide is purified when it constitutes at least 60 (e.g., at least65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the totalprotein in a sample.

An amino acid residue in a protein “corresponds” to a given residue whenit occupies the same essential structural position within the protein asthe given residue. For example, a selected residue in a selected proteincorresponds to a particular amino acid in HER3 when the selected residueoccupies the same essential spatial or other structural relationship asparticular amino acid in HER3. In some embodiments, where a selectedprotein is aligned for maximum homology with the human HER3 protein, theposition in the aligned selected protein aligning with a particularreside is said to correspond to that particular reside. Instead of aprimary sequence alignment, a three dimensional structural alignment canalso be used, e.g., where the structure of the selected protein isaligned for maximum correspondence with the human HER3 protein and theoverall structures compared. In this case, an amino acid that occupiesthe same essential position as a particular reside in the structuralmodel is said to correspond to the particular reside.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethylcellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches. etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g. anti-canceragent). The compound of the invention can be administered alone or canbe coadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation, to increasedegradation of a prodrug and release of the drug, detectable agent). Thecompositions of the present invention can be delivered by transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., reducing, eliminating, or slowing theprogression of disease symptoms (e.g. symptoms of cancer or aberrantHER3 activity). Determination of a therapeutically effective amount of acompound of the invention is well within the capabilities of thoseskilled in the art, especially in light of the detailed disclosureherein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g. symptoms of cancer), kind of concurrent treatment,complications from the disease being treated or other health-relatedproblems. Other therapeutic regimens or agents can be used inconjunction with the methods and compounds of Applicants' invention.Adjustment and manipulation of established dosages (e.g., frequency andduration) are well within the ability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer,or with adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent within 0.5, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In someembodiments, the compounds described herein may be combined withtreatments for cancer such as radiation or surgery.

As used herein, the term “about” means a range of values including thespecified value, which a person of ordinary skill in the art wouldconsider reasonably similar to the specified value. In embodiments,about means within a standard deviation using measurements generallyacceptable in the art. In embodiments, about means a range extending to+/−10% of the specified value. In embodiments, about includes thespecified value.

The term “Receptor tyrosine-protein kinase erbB-3”, “human epidermalgrowth factor receptor 3”, “ERBB3”, or “HER3” refers to a pseudokinase(reduced activity or inactive kinase) that s a member of the epidermalgrowth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases.The term “HER3” may refer to the nucleotide sequence or protein sequenceof human HER3 (e.g., Entrez 2065, Uniprot P21860, RefSeq NM_001982, orRefSeq NP_001973). The term “HER3” includes both the wild-type form ofthe nucleotide sequences or proteins as well as any mutants thereof. Insome embodiments, “HER3” is wild-type HER3 receptor. In someembodiments, “HER3” is one or more mutant forms. The term “HER3” XYZrefers to a nucleotide sequence or protein of a mutant HER3 wherein theY numbered amino acid of HER3 that normally has an X amino acid in thewildtype, instead has a Z amino acid in the mutant. In embodiments, anHER3 is the human HER3. In embodiments, the HER3 has the nucleotidesequence corresponding to reference number GI:317171925. In embodiments,the HER3 has the nucleotide sequence corresponding to RefSeqNM_001982.3. In embodiments, the HER3 has the protein sequencecorresponding to reference number GI:54792100. In embodiments, the HER3has the protein sequence corresponding to RefSeq NP_001973.2. Inembodiments, the HER3 has the following amino acid sequence:

(SEQ ID NO: 1) MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVMGNLEIVLTGHNADLSFLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAIFVMLNYNTNSSHALRQLRLTQLTEILSGGVYIEKNDKLCHMDTIDWRDIVRDRDAEIVVKDNGRSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQCCHDECAGGCSGPQDTDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTSCVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGNLDFLITGLNGDPWHKIPALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGGRSLYNRGFSLLIMKNLNVTSLGFRSLKEISAGRIYISANRQLCYHHSLNWTKVLRGPTEERLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSRGGVCVTHCNFLNGEPREFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPIYKYPDVGNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLGGTFLYWRGRRIQNKRAMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVFGTVHKGVWIPEGESIKIPVCIKVIEDKSGRQSFQAVTDHMLAIGSLDHAHIVRLLGLCPGSSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYLEEHGMVHRNLAARNVLLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVTVWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKELANEFTRMARDPPRYLVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEEDNLATTTLGSALSLPVGTLNRPRGSQSLLSPSSGYMPMNQGNLGESCQESAVSGSSERCPRPVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPRPRGDSAYHSQRHSLLTPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYMNRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDYEYMNRQRDGGGPGGDYAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATDSAFDNPDYWHSRLFPKANAQRT.

In embodiments, the HER3 is a mutant HER3. In embodiments, the mutantHER3 is associated with a disease that is not associated with wildtypeHER3. In embodiments, the HER3 includes at least one amino acid mutation(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared tothe sequence above. In embodiments, the HER3 is a variant of thesequence above, including a shorter variant or mutated variant. Inembodiments, the mutant HER3 is a splice variant. In embodiments, themutant HER3 is a splice variant with aberrant activity relative to thewildtype HER3. In embodiments, the mutant HER3 is a truncated splicevariant with aberrant activity relative to the wildtype HER3. Inembodiments, the mutant HER3 is a splice variant lacking a portion ofthe wildtype HER3 with aberrant activity relative to the wildtype HER3.In embodiments, the HER3 is described in Cancer Cell (2013) May 13 23,603-617, which is herein incorporated in its entirety for all purposes.

The term “Receptor tyrosine-protein kinase erbB-2”, “human epidermalgrowth factor receptor 2”, “CD340”, “ERBB2”, “neu”, “HER2/neu”, or“HER2” refers to a member of the epidermal growth factor receptor(EGFR/ERBB) family of receptor tyrosine kinases. The term “HER2” mayrefer to the nucleotide sequence or protein sequence of human HER2(e.g., Entrez 2064, Uniprot P04626, RefSeq NM_004448, or RefSeqNP_004439). The term “HER2” includes both the wild-type form of thenucleotide sequences or proteins as well as any mutants thereof. In someembodiments, “HER2” is wild-type HER3 receptor. In some embodiments,“HER2” is one or more mutant forms. The term “HER2” XYZ refers to anucleotide sequence or protein of a mutant HER2 wherein the Y numberedamino acid of HER2 that normally has an X amino acid in the wildtype,instead has a Z amino acid in the mutant. In embodiments, an HER2 is thehuman HER2. In embodiments, the HER2 has the nucleotide sequencecorresponding to reference number GI:584277099. In embodiments, the HER2has the nucleotide sequence corresponding to RefSeq NM_004448.3. Inembodiments, the HER2 has the protein sequence corresponding toreference number GI:54792096. In embodiments, the HER2 has the proteinsequence corresponding to RefSeq NP_004439.2. In embodiments, the HER2has the following amino acid sequence:

(SEQ ID NO: 2) MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVGILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFTHQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQPEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEY LGLDVPV.

In embodiments, the HER2 is a mutant HER2. In embodiments, the mutantHER2 is associated with a disease that is not associated with wildtypeHER2. In embodiments, the HER2 includes at least one amino acid mutation(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared tothe sequence above. In embodiments, the HER2 is a variant of thesequence above, including a shorter variant or mutated variant. Inembodiments, the mutant HER2 is a splice variant. In embodiments, themutant HER2 is a splice variant with aberrant activity relative to thewildtype HER2. In embodiments, the mutant HER2 is a truncated splicevariant with aberrant activity relative to the wildtype HER2. Inembodiments, the mutant HER2 is a splice variant lacking a portion ofthe wildtype HER2 with aberrant activity relative to the wildtype HER2.

The term “ligand” is used in accordance with its plain ordinary meaningand refers to a molecule (e.g., compound as described herein) capable ofbinding to another molecule (e.g., protein, receptor, enzyme, target, orcell). In embodiments, a ligand is a modulator, inhibitor, activator,agonist, or antagonist.

Provided herein are agents (e.g. compounds, drugs, therapeutic agents)that may be in a prodrug form. Prodrugs of the compounds describedherein are those compounds that readily undergo chemical changes underselect physiological conditions to provide the final agents (e.g.compounds, drugs, therapeutic agents). Additionally, prodrugs can beconverted to agents (e.g. compounds, drugs, therapeutic agents) bychemical or biochemical methods in an ex vivo environment. Prodrugsdescribed herein include compounds that readily undergo chemical changesunder select physiological conditions to provide agents (e.g. compounds,drugs, prophylactic agents, therapeutic agents) to a biological system(e.g. in a subject, in a cancer cell, in the extracellular space near acancer cell). For example, physiologically hydrolyzable esters or amidesare esters or amides, respectively, that are hydrolyzed to thecorresponding hydroxyl and carboxylic acid portions of the ester, or thecorresponding amine and carboxylic acid portions of the amide, by achemical or enzymatic reaction (e.g., esterase or amidase or protease)following administration to a subject.

“Analog” and “analogue” are used interchangeably and are used inaccordance with their plain ordinary meaning within Chemistry andBiology and refers to a chemical compound that is structurally similarto another compound (i.e., a so-called “reference” compound) but differsin composition, e.g., in the replacement of one atom by an atom of adifferent element, or in the presence of a particular functional group,or the replacement of one functional group by another functional group,or the absolute stereochemistry of one or more chiral centers of thereference compound, including isomers thereof or but differs in one ormore components (e.g., different substituent(s), addition ofsubstituent(s), removal of substituent(s)). Accordingly, an analog is acompound that is similar or comparable in function and appearance butnot in structure or origin to a reference compound.

The term “derivative” is used in accordance with its plain ordinarymeaning in Chemistry and refers to a compound that is derived (e.g., aproduct made from a reactant) from a similar compound by a chemical orphysical process. “Derivative” is used in accordance with its plainordinary meaning within Chemistry and Biology and refers to a compound(e.g., chemical) that is structurally similar to another compound (i.e.,a so-called “reference” compound) but differs in composition, e.g., inthe replacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound,including isomers thereof; and the derivative is a compound that wasderived from the reference compound through one or more chemicalreaction(s) or the reference compound was derived from the derivativethrough one or more chemical reaction(s). Accordingly, a derivative is acompound that is similar or comparable in function and appearance butnot in structure or origin to a reference compound. In embodiments of aderivative, an original substituent (e.g., substituent group) of areference compound is replaced with an alternative substituent (e.g.,substituent group), wherein the alternative substituent (e.g.,substituent group) is different from the original substituent (e.g.,substituent group). In embodiments of a derivative, a plurality oforiginal substituents substituent groups) of a reference compound arereplaced with a plurality of alternative substituents (e.g., substituentgroups), wherein the alternative substituents (e.g., substituent groups)are each optionally different and each alternative substituent (e.g.,substituent group) is different from the original substituent (e.g.,substituent group) it replaces. In embodiments of a derivative, ahydrogen atom of a reference compound is replaced with a substituent(e.g., substituent group). In embodiments of a derivative, a pluralityof hydrogen atoms of a reference compound are replaced with a pluralityof substituents (e.g., substituent groups), wherein the substituents(e.g., substituent groups) are each optionally different.

The term “HER3 activity” is used in accordance with its plain ordinarymeaning and refers to the function or activity of the HER3 protein.Examples of HER3 activity include dimerization (e.g., heterodimerizationor activation of the activity of a protein upon dimerization with HER3(e.g., EGFR activity, HER2 activity, HER4 activity, or c-MET activity).In embodiments, HER3 activity is increasing or activating activity of aprotein interacting with HER3 (e.g., PI3K activity, MEK activity, MAPKactivity, RAF activity, BRAF activity, AKT activity, RAS activity, orKRAS activity). In embodiments HER3 activity is activation or increasingof activity of a signaling pathway by HER3 or activation of a componentof a signaling pathway by HER3 (e.g., directly or through interveningcomponents of the signaling pathway). In embodiments HER3 activity isactivation of kinase activity of a protein that interacts (e.g.,directly contacting HER3 or interactions with HER3 throughintermediates) with HER3 (e.g., EGFR, HER2, HER4, c-MET, PI3K, MEK,MAPK, RAF, BRAF, AKT, RAS, or KRAS).

The term “degradation-increasing moiety” is used in accordance with itsplain ordinary meaning and refers to a moiety capable of increasing thedegradation of a protein or other biological molecule (e.g., includingby binding to the protein or other biological molecule or by binding tothe protein or other biological molecule through a second moiety bondedto the degradation-increasing moiety (e.g., wherein thedegradation-increasing moiety and second moiety are a compound describedherein and the protein or other biological molecule bound to thecompound described herein is a HER protein, for example HER3, and theHER protein (e.g., HER3) is degraded more than control (e.g.,degradation in the absence of the compound including thedegradation-increasing moiety)). In embodiments, adegradation-increasing moiety increases the interaction of a protein tobe degraded with a cell's protein degradation components (e.g.,ubiquitin ligase(s), proteasome, E3 ubiquitin ligase (e.g., cereblon,HECT, RING-finger, U-box, PHD-finger, APC, SCF complex(Skp1-Cullin-F-box protein complex), E3A, mdm2, EDD1, SOCS, LNXp80,CBX4, HACE1, CBLL1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2,HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2,PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12,UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, VHL, orVHL-cullin-RING-ligase complex). In embodiments, thedegradation-increasing moiety binds (e.g., directly or through anothermoiety bonded to the degradation-increasing moiety (e.g., anotherportion of a compound that includes a degradation-increasing moiety)) tothe protein to be degraded and a component of the cell's proteindegradation effectors (e.g., E3 ubiquitin ligase). In embodiments, thedegradation-increasing moiety is a thalidomide moiety or an analog,derivative, or prodrug thereof; phthalimide moiety or an analog,derivative, or prodrug thereof; adamantyl or an analog, derivative, orprodrug thereof; an IκBα phosphopeptide moiety or an analog, derivative,or prodrug thereof; nutlin moiety or an analog, derivative, or prodrugthereof; HIF-1α pentapeptide moiety or an analog, derivative, or prodrugthereof; or

or an analog, derivative, or prodrug thereof. In embodiments, thedegradation-increasing moiety is described in Bioorg. Med. Chem. Lett(2008) 18 5904-5908; Cancer Cell (2011) August 16, 20, 158-172; Nat ChemBiol (2014) December vol 10, 1006-1012; Nat Chem Biol (2015) August vol11 611-617; Oncogene (2008) 27, 7201-7211; P. Natl Acad Sci USA (2001)July 17, vol. 98(15) 8554-8559; Science (2015) 348, 1376-1381; U.S. Pat.No. 7,208,157; U.S. Pat. No. 7,041,298; US publ. no. 20150119435; USpubl. no. 20040038358; or US publ. no. 20020068063, all of which areherein incorporated by reference in their entirely and for all purposes.

B. COMPOUNDS

In an aspect is provided a compound having the formula:

Ring A is aryl or heteroaryl. W¹ is N or C(R⁶). R¹ is independently ahalogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸,—NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸,—C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹,—NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R¹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, R⁴ is independently a hydrogen,halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴ ₂, degradation-increasingmoiety, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁵ is independently a hydrogen,halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵,degradation-increasing moiety, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted or substituted or unsubstituted heteroaryl. R⁶ isindependently a hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶₃, —OCHX⁶ ₂, —OCH₂X⁶, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁷, R⁸,R⁹, and R¹⁰ are independently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂,—CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. L⁴ is a bond or a divalent linker. L⁵ is a bond or adivalent linker. z1 is independently an integer from 0 to 7. m1 and v1are independently 1 or 2. n1 is independently an integer from 0 to 4.X¹, X⁴, X⁵, X⁶, and X^(A) are independently —Cl, —Br, —I, or —F. Inembodiments, one of R⁴ and R⁵ is a degradation-increasing moiety (e.g.,as described herein, including in an embodiment). In embodiments, R⁴ isa degradation-increasing moiety (e.g., as described herein, including inan embodiment). In embodiments, R⁵ is a degradation-increasing moiety(e.g., as described herein, including in an embodiment). In embodiments,R⁴ and R⁵ are independently an optionally differentdegradation-increasing moiety (e.g., as described herein, including inan embodiment). In embodiments, R⁴ is a degradation-increasing moietyselected from a thalidomide moiety or an analog, derivative, or prodrugthereof; phthalimide moiety or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide moiety or an analog, derivative, or prodrug thereof;nutlin moiety or an analog, derivative, or prodrug thereof; and HIF-1αpentapeptide moiety or an analog, derivative, or prodrug thereof; and

or an analog, derivative, or prodrug thereof. In embodiments, R⁵ is adegradation-increasing moiety selected from a thalidomide moiety or ananalog, derivative, or prodrug thereof; phthalimide moiety or an analog,derivative, or prodrug thereof; adamantyl or an analog, derivative, orprodrug thereof; an IκBα phosphopeptide moiety or an analog, derivative,or prodrug thereof; nutlin moiety or an analog, derivative, or prodrugthereof; and HIF-1α pentapeptide moiety or an analog, derivative, orprodrug thereof; and

or an analog, derivative, or prodrug thereof.

In an aspect is provided a compound having the formula:

Ring A is aryl or heteroaryl. Ring B is aryl or heteroaryl. W¹ is N orC(R⁶). R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, —OCH₂X¹, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R¹ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² is independently a halogen, —CX² ₃, —CHX²₂, —CH₂X², —CN, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹²,—NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹², —C(O)R¹³,—C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX² ₃, —OCHX² ₂, —OCH₂X², substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R² substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁴ is independently a hydrogen,halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₄H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴ ₂,degradation-increasing moiety, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁵ isindependently a hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵₃, —OCHX⁵ ₂, —OCH₂X⁵, degradation-increasing moiety, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁶ is independently a hydrogen, halogen, —CX⁶₃, —CHX⁶ ₂, —CH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁷, R⁸, R⁹, ¹⁰, R¹¹, R¹², R¹³, and R¹⁴ areindependently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁷ and R⁸ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R¹¹ and R¹²substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl. L¹ is a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted alkylene or substituted or unsubstituted heteroalkylene.L⁴ is a bond or a divalent linker. L⁵ is a bond or a divalent linker. z1and z2 are independently an integer from 0 to 7. m1, m2, v1, and v2 areindependently 1 or 2. n1 and n2 are independently an integer from 0 to4. X¹, X², X⁴, X⁵, X⁶, and X^(A) are independently —Cl, —Br, —I, or —F.

In embodiments, the compound has the formula:

Ring A, Ring B, W¹, R¹, R², R⁴, R⁵, L¹, L⁴, L⁵, X¹, X², X⁴, X⁵, X⁶,X^(A), z1, and z2 are as described herein.

Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Inembodiments, ring C is C₃-C₆ cycloalkyl, 3 to 6 memberedheterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl. R³ isindependently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN, —SO_(n3)R¹⁸,—SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵R¹⁶,—N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸,—NR¹⁵SO₂R¹⁷, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX³ ₃, —OCHX³₂, —OCH₂X³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl twoadjacent R³ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independentlyhydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁵and R¹⁶ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl. L² is a bond, —O—, —NH—,—C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—,substituted or unsubstituted alkylene or substituted or unsubstitutedheteroalkylene. In embodiments, L² is a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted C₁-C₃ alkylene or substituted or unsubstituted 2 to 3membered heteroalkylene. z3 is independently an integer from 0 to 5. m3is independently 1 or 2. v3 is independently 1 or 2. n3 s independentlyan integer from 0 to 4. X³ is independently —Cl, —Br, —I, or —F.

In embodiments, Ring A is phenyl. In embodiments, Ring A is a 5 to 6membered heteroaryl. In embodiments, Ring A is a thienyl. Inembodiments, Ring A is a 2-thienyl. In embodiments, Ring A is a3-thienyl. In embodiments, Ring A is a pyridyl. In embodiments, Ring Ais a 2-pyridyl. In embodiments, Ring A is a 3-pyridyl. In embodiments,Ring A is a 4-pyridyl. In embodiments, Ring A is a napththyl. Inembodiments, Ring A is a 1-napththyl. In embodiments, Ring A is a2-napththyl. In embodiments, Ring A is a quinolinyl. In embodiments,Ring A is a isoquinolinyl. In embodiments, Ring A is a 1-isoquinolinyl.In embodiments, Ring A is a 3-isoquinolinyl. In embodiments, Ring A is a4-isoquinolinyl. In embodiments, Ring A is phenyl or 5 or 6 memberedheteroaryl. In embodiments, the numbering of Ring A in this paragraph(e.g., 2-thienyl, 1-isoquinolinyl, etc.) refers the attachment point ofthe —NH— linker that connects Ring A to the fused ring moiety (i.e. thefused ring that contains W¹).

In embodiments,

is

In embodiments,

is

wherein R^(1.2) and R^(1.4) are halogen, and R^(1.5) is unsubstitutedmethoxy. In embodiments, z1 is 0. In embodiments, Ring A is aryl when z1is non-zero. In embodiments, Ring A is a heteroaryl when z1 is non-zero.In embodiments, Ring A is a aryl (e.g., C₆-C₁₀ or phenyl) or 5 to 6membered heteroaryl when z1 is non-zero. In embodiments, Ring A is aryl(e.g., C₆-C₁₀ or phenyl) when z1 is non-zero. In embodiments, Ring A is5 to 6 membered heteroaryl when z1 is non-zero.

In embodiments, Ring B is phenyl. In embodiments, Ring B is a 5 to 6membered heteroaryl. In embodiments, Ring B is a thienyl. Inembodiments, Ring B is a 2-thienyl. In embodiments, Ring B is a3-thienyl. In embodiments, Ring B is a pyridyl. In embodiments, Ring Bis a 2-pyridyl. In embodiments, Ring B is a 3-pyridyl. In embodiments,Ring B is a 4-pyridyl. In embodiments, Ring B is a napththyl. Inembodiments, Ring B is a 1-napththyl. In embodiments, Ring B is a2-napththyl. In embodiments, Ring B is a quinolinyl. In embodiments,Ring B is a isoquinolinyl. In embodiments, Ring B is a 1-isoquinolinyl.In embodiments, Ring B is a 3-isoquinolinyl. In embodiments, Ring B is a4-isoquinolinyl. In embodiments, Ring B is phenyl or 5 or 6 memberedheteroaryl. In embodiments, the numbering of Ring B in this paragraph(e.g., 2-thienyl, 1-isoquinolinyl, etc.) refers the attachment point ofthe L¹ linker that connects Ring B to Ring A.

In embodiments, Ring B is

In embodiments, Ring B is

In embodiments, Ring B is

In embodiments, Ring B is

In embodiments, Ring B is a substituted aryl or substituted heteroaryl.In embodiments, Ring B is a substituted aryl. In embodiments, Ring B isa substituted heteroaryl. In embodiments, Ring B is a substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, Ring B is pyridyl when z2 is 1. Inembodiments, Ring B is pyridyl when z2 is 2.

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

In embodiments,

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

when W¹ is N. In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments, Ring C is cycloalkyl. In embodiments, Ring C isheterocycloalkyl. In embodiments, Ring C is aryl. In embodiments, Ring Cis heteroaryl. In embodiments, Ring C is phenyl. In embodiments, Ring Cis a 5 to 6 membered heteroaryl. In embodiments, Ring C is a thienyl. Inembodiments, Ring C is a 2-thienyl. In embodiments, Ring C is a3-thienyl. In embodiments, Ring C is a pyridyl. In embodiments, Ring Cis a 2-pyridyl. In embodiments, Ring C is a 3-pyridyl. In embodiments,Ring C is a 4-pyridyl. In embodiments, Ring C is a C₃-C₆ cycloalkyl. Inembodiments, Ring C is a C₃ cycloalkyl. In embodiments, Ring C is a C₄cycloalkyl. In embodiments, Ring C is a C₅ cycloalkyl. In embodiments,Ring C is a C₆ cycloalkyl. In embodiments, Ring C is a 3 memberedheterocycloalkyl. In embodiments, Ring C is a 4 memberedheterocycloalkyl. In embodiments, Ring C is a 5 memberedheterocycloalkyl. In embodiments, Ring C is a 6 memberedheterocycloalkyl. In embodiments, the numbering of Ring C in thisparagraph (e.g., 2-thienyl, 1-isoquinolinyl, etc.) refers the attachmentpoint of the L² linker that connects Ring C to Ring B.

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments,

is

In embodiments, R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstitutedC₁-C₄ alkyl, or substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R¹ is independently halogen, —CF₃, —CHF₂,—OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₃ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R¹ is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R¹ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R¹ is independently halogen. In embodiments, R¹is independently —CF₃. In embodiments, R¹ is independently —CHF₂. Inembodiments, R¹ is independently —CH₂F. In embodiments, R¹ isindependently —OCF₃. In embodiments, R¹ is independently —OCHF₂. Inembodiments, R¹ is independently —OCH₂F. In embodiments, R¹ isindependently substituted or unsubstituted C₁-C₈ alkyl. In embodiments,R¹ is independently substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, R¹ is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹ is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R¹ is independently substituted or unsubstituted 5to 10 membered heteroaryl. In embodiments, R¹ is independently —OH. Inembodiments, R¹ is independently —NH₂. In embodiments, R¹ isindependently —SH. In embodiments, R¹ is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R¹ is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R¹ is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹ isindependently substituted or unsubstituted phenyl. In embodiments, R¹ isindependently substituted or unsubstituted 5 to 6 membered heteroaryl.In embodiments, R¹ is independently substituted C₁-C₈ alkyl. Inembodiments, R¹ is independently substituted 2 to 8 memberedheteroalkyl. In embodiments, R¹ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹ is independentlysubstituted C₆-C₁₀ aryl. In embodiments, R¹ is independently substituted5 to 10 membered heteroaryl. In embodiments, R¹ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R¹ is independently substituted2 to 4 membered heteroalkyl. In embodiments, R¹ is independentlysubstituted C₃-C₆ cycloalkyl. In embodiments, R¹ is independentlysubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹ isindependently substituted phenyl. In embodiments, R¹ is independentlysubstituted 5 to 6 membered heteroaryl. In embodiments, R¹ isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R¹ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R¹ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R¹ is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R¹ is independently unsubstituted C₁-C₄alkyl. In embodiments, R¹ is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R¹ is independently unsubstituted C₃-C₆cycloalkyl. In embodiments, R¹ is independently unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R¹ is independentlyunsubstituted phenyl. In embodiments, R¹ is independently unsubstituted5 to 6 membered heteroaryl. In embodiments, R¹ is independentlyunsubstituted methyl. In embodiments, R¹ is independently unsubstitutedethyl. In embodiments, R¹ is independently unsubstituted isopropyl. Inembodiments, R¹ is independently unsubstituted tert-butyl. Inembodiments, R¹ is independently unsubstituted methoxy. In embodiments,R¹ is independently unsubstituted ethoxy. In embodiments, R¹ isindependently —F. In embodiments, R¹ is independently —Cl. Inembodiments, R¹ is independently —Br. In embodiments, R¹ isindependently —I. In embodiments, R¹ is independently hydrogen.

In embodiments, z1 is 1. In embodiments, z1 is 0. In embodiments, z1 is2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1is an integer from 0 to 4. In embodiments, z1 and z2 are 0. Inembodiments, z1 is an integer from 0 to 1.

In embodiments, R² is independently a halogen, —CX² ₃, —CHX² ₂, —CH₂X²,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstitutedC₁-C₄ alkyl, or substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R² is independently halogen, —CF₃, —CHF₂,—OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R² is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R² isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R² isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R² is independently halogen. In embodiments, R²is independently —CF₃. In embodiments, R² is independently —CHF₂. Inembodiments, R² is independently —CH₂F. In embodiments, R² isindependently —OCF₃. In embodiments, R² is independently —OCHF₂. Inembodiments, R² is independently —OCH₂F. In embodiments, R² isindependently substituted or unsubstituted C₁-C₈ alkyl. In embodiments,R² is independently substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, R² is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R² is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R² is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R² is independently substituted or unsubstituted 5to 10 membered heteroaryl. In embodiments, R² is independently —OH. Inembodiments, R² is independently —NH₂. In embodiments, R² isindependently —SH. In embodiments, R² is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R² is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R² is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R² is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R² isindependently substituted or unsubstituted phenyl. In embodiments, R² isindependently substituted or unsubstituted 5 to 6 membered heteroaryl.In embodiments, R² is independently substituted C₁-C₈ alkyl. Inembodiments, R² is independently substituted 2 to 8 memberedheteroalkyl. In embodiments, R² is independently substituted C₃-C₈cycloalkyl. In embodiments, R² is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R² is independentlysubstituted C₆-C₁₀ aryl. In embodiments, R² is independently substituted5 to 10 membered heteroaryl. In embodiments, R² is independentlysubstituted C₁-C₄ alkyl. In embodiments, R² is independently substituted2 to 4 membered heteroalkyl. In embodiments, R² is independentlysubstituted C₃-C₆ cycloalkyl. In embodiments, R² is independentlysubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R² isindependently substituted phenyl. In embodiments, R² is independentlysubstituted 5 to 6 membered heteroaryl. In embodiments, R² isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R² isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R² is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R²is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R² is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R² is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R² is independently unsubstituted C₁-C₄alkyl. In embodiments, R² is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R² is independently unsubstituted C₃-C₆cycloalkyl. In embodiments, R² is independently unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R² is independentlyunsubstituted phenyl. In embodiments, R² is independently unsubstituted5 to 6 membered heteroaryl. In embodiments, R² is independentlyunsubstituted methyl. In embodiments, R² is independently unsubstitutedethyl. In embodiments, R² is independently unsubstituted isopropyl. Inembodiments, R² is independently unsubstituted tert-butyl. Inembodiments, R² is independently unsubstituted methoxy. In embodiments,R² is independently unsubstituted ethoxy. In embodiments, R² isindependently —F. In embodiments, R² is independently —Cl. Inembodiments, R² is independently —Br. In embodiments, R² isindependently —I. In embodiments, R² is independently hydrogen.

In embodiments, z2 is 1. In embodiments, z2 is 0. In embodiments, z2 is2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2is 5. In embodiments, z2 is an integer from 0 to 4. In embodiments, z2is an integer from 0 to 1.

In embodiments, R³ is independently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstitutedC₁-C₄ alkyl, or substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R³ is independently halogen, —CF₃, —CHF₂,—CH₂F, —OCHF₂, —OCHF₂, —OCH₂F, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R³ is independently halogen, —CF₃, —CHF₂, —OCF₃, —OCHF₂,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2to 8 membered heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R³ is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₃-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R³ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R³ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R³ is independently halogen. In embodiments, R³is independently —CF₃. In embodiments, R³ is independently —CHF₂. Inembodiments, R³ is independently —CH₂F. In embodiments, R³ isindependently —OCF₃. In embodiments, R³ is independently —OCHF₂. Inembodiments, R³ is independently —OCH₂F. In embodiments, R³ isindependently substituted or unsubstituted C₁-C₈ alkyl. In embodiments,R³ is independently substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, R³ is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R³ is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R³ is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R³ is independently substituted or unsubstituted 5to 10 membered heteroaryl. In embodiments, R³ is independently —OH. Inembodiments, R³ is independently —NH₂. In embodiments, R³ isindependently —SH. In embodiments, R³ is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R³ is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R³ is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R³ is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R³ isindependently substituted or unsubstituted phenyl. In embodiments, R³ isindependently substituted or unsubstituted 5 to 6 membered heteroaryl.In embodiments, R³ is independently substituted C₁-C₈ alkyl. Inembodiments, R³ is independently substituted 2 to 8 memberedheteroalkyl. In embodiments, R³ is independently substituted C₃-C₈cycloalkyl. In embodiments, R³ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R³ is independentlysubstituted C₆-C₁₀ aryl. In embodiments, R³ is independently substituted5 to 10 membered heteroaryl. In embodiments, R³ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R³ is independently substituted2 to 4 membered heteroalkyl. In embodiments, R³ is independentlysubstituted C₃-C₆ cycloalkyl. In embodiments, R³ is independentlysubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R³ isindependently substituted phenyl. In embodiments, R³ is independentlysubstituted 5 to 6 membered heteroaryl. In embodiments, R³ isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R³ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R³ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R³is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R³ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R³ is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R³ is independently unsubstituted C₁-C₄alkyl. In embodiments, R³ is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R³ is independently unsubstituted C₃-C₆cycloalkyl. In embodiments, R³ is independently unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R³ is independentlyunsubstituted phenyl. In embodiments, R³ is independently unsubstituted5 to 6 membered heteroaryl. In embodiments, R³ is independentlyunsubstituted methyl. In embodiments, R³ is independently unsubstitutedethyl. In embodiments, R³ is independently unsubstituted isopropyl. Inembodiments, R³ is independently unsubstituted tert-butyl. Inembodiments, R³ is independently unsubstituted methoxy. In embodiments,R³ is independently unsubstituted ethoxy. In embodiments, R³ isindependently —F. In embodiments, R³ is independently —Cl. Inembodiments, R³ is independently —Br. In embodiments, R³ isindependently —I. In embodiments, R³ is independently hydrogen. Inembodiments, R³ is —CF₃. In embodiments, R³ is a halogen.

In embodiments, z3 is 1. In embodiments, z3 is 0. In embodiments, z3 is2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3is 5.

In embodiments, R⁴ is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R⁴ is independently halogen, —CF₃, —CHF₂, —OCF₃, —OCHF₂,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2to 8 membered heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R⁴ is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁴ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R⁴ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R⁴ is independently halogen. In embodiments, R⁴is independently —CF₃. In embodiments, R⁴ is independently —CHF₂. Inembodiments, R⁴ is independently —CH₂F. In embodiments, R⁴ isindependently —OCF₃. In embodiments, R⁴ is independently —OCHF₂. Inembodiments, R⁴ is independently —OCH₂F. In embodiments, R⁴ isindependently substituted or unsubstituted C₁-C₈ alkyl. In embodiments,R⁴ is independently substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, R⁴ is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁴ is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R⁴ is independently substituted or unsubstituted 5to 10 membered heteroaryl. In embodiments, R⁴ is independently —OH. Inembodiments, R⁴ is independently —NH₂. In embodiments, R⁴ isindependently —SH. In embodiments, R⁴ is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R⁴ is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R⁴ is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R⁴ isindependently substituted or unsubstituted phenyl. In embodiments, R⁴ isindependently substituted or unsubstituted 5 to 6 membered heteroaryl.In embodiments, R⁴ is independently substituted C₁-C₈ alkyl. Inembodiments, R⁴ is independently substituted 2 to 8 memberedheteroalkyl. In embodiments, R⁴ is independently substituted C₃-C₈cycloalkyl. In embodiments, R⁴ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R⁴ is independentlysubstituted C₆-C₁₀ aryl. In embodiments, R⁴ is independently substituted5 to 10 membered heteroaryl. In embodiments, R⁴ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R⁴ is independently substituted2 to 4 membered heteroalkyl. In embodiments, R⁴ is independentlysubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴ is independentlysubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R⁴ isindependently substituted phenyl. In embodiments, R⁴ is independentlysubstituted 5 to 6 membered heteroaryl. In embodiments, R⁴ isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R⁴ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R⁴ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁴is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁴ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R⁴ is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R⁴ is independently unsubstituted C₁-C₄alkyl. In embodiments, R⁴ is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴ is independently unsubstituted C₃-C₆cycloalkyl. In embodiments, R⁴ is independently unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴ is independentlyunsubstituted phenyl. In embodiments, R⁴ is independently unsubstituted5 to 6 membered heteroaryl. In embodiments, R⁴ is —NH₂.

In embodiments, -L⁴-R⁴ is unsubstituted methoxy.

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is

In embodiments, -L⁴-R⁴ is substituted or unsubstituted 5 to 10 memberedheteroalkyl. In embodiments, -L⁴-R⁴ is substituted or unsubstituted 6 to10 membered heteroalkyl. In embodiments, -L⁴-R⁴ is substituted orunsubstituted 7 to 10 membered heteroalkyl. In embodiments, -L⁴-R⁴ issubstituted or unsubstituted 7 to 9 membered heteroalkyl. Inembodiments, -L⁴-R⁴ is substituted or unsubstituted 5 memberedheteroaryl. In embodiments, -L⁴-R⁴ is substituted or unsubstituted 5 to6 membered heteroaryl. In embodiments, -L⁴-R⁴ is substituted orunsubstituted 4 to 6 membered heteroaryl. In embodiments, -L⁴-R⁴ issubstituted or unsubstituted heteroaryl. In embodiments, -L⁴-R⁴ issubstituted 5 membered heteroaryl. In embodiments, -L⁴-R⁴ is substituted5 to 6 membered heteroaryl. In embodiments, -L⁴-R⁴ is substituted 4 to 6membered heteroaryl. In embodiments, -L⁴-R⁴ is substituted heteroaryl.In embodiments, -L⁴-R⁴ is unsubstituted 5 membered heteroaryl. Inembodiments, -L⁴-R⁴ is unsubstituted 5 to 6 membered heteroaryl. Inembodiments, -L⁴-R⁴ is unsubstituted heteroaryl. In embodiments, -L⁴-R⁴is unsubstituted 4 to 6 membered heteroaryl.

In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety. In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety. In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety. In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety. In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety. In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety. In embodiments, -L⁴-R⁴ is

when R⁵ is a degradation-increasing moiety.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is thalidomide moiety or an analog,derivative, or prodrug thereof; phthalimide moiety or an analog,derivative, or prodrug thereof; adamantyl or an analog, derivative, orprodrug thereof; an IκBα phosphopeptide moiety or an analog, derivative,or prodrug thereof; nutlin moiety or an analog, derivative, or prodrugthereof; HIF-1α pentapeptide moiety or an analog, derivative, or prodrugthereof; or

or an analog, derivative, or prodrug thereof. In embodiments, thedegradation-increasing moiety is thalidomide moiety or an analog,derivative, or prodrug thereof. In embodiments, R⁴ is

or an analog, derivative, or prodrug thereof. In embodiments, R⁴ is

In embodiments, R⁴ is a thalidomide moiety or an analog, derivative, orprodrug thereof. In embodiments, R⁴ is a thalidomide moiety. Inembodiments, R⁴ is a lenalidomide moiety. In embodiments, R⁴ is apomalidomide moiety. In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is a phthalimide moiety or an analog, derivative, orprodrug thereof. In embodiments, R⁴ is

In embodiments, R⁴ is

In embodiments, R⁴ is a phthalimide moiety. In embodiments, R⁴ includesa thalidomide moiety or an analog, derivative, or prodrug thereof. Inembodiments, R⁴ includes a thalidomide moiety. In embodiments, R⁴includes a lenalidomide moiety. In embodiments, R⁴ includes apomalidomide moiety. In embodiments, R⁴ includes a phthalimide moiety oran analog, derivative, or prodrug thereof. In embodiments, R⁴ includes aphthalimide moiety.

In embodiments, R⁴ is adamantyl or an analog, derivative, or prodrugthereof. In embodiments, R⁴ is substituted adamantyl or an analog,derivative, or prodrug thereof. In embodiments, R⁴ is adamantyl. Inembodiments, R⁴ is substituted adamantyl.

In embodiments, R⁴ is a phosphopeptide including a sequence of IκBα, oran analog, derivative, or prodrug thereof. In embodiments, R⁴ is aphosphopeptide consisting of a sequence of IκBα, or an analog,derivative, or prodrug thereof. In embodiments, R⁴ is -RAEDS*GNES*EGE(SEQ ID NO:3) or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein S* is aphosphoserine. In embodiments, R⁴ is -RAEDS*GNES*EGE (SEQ ID NO:3). Inembodiments, R⁴ is -G₀₋₁₀RAEDS*GNES*EGE (SEQ ID NO:4) or a derivativethereof (e.g., including one, two or three substitutions (e.g.,conservative substitutions), wherein S* is a phosphoserine. Inembodiments, R⁴ is -G₀₋₁₀RAEDS*GNES*EGE (SEQ ID NO:4). In embodiments,R⁴ is -DRIIDS*GLDS*M (SEQ ID NO:5) or a derivative thereof (e.g.,including one, two or three substitutions (e.g., conservativesubstitutions), wherein S* is a phosphoserine. In embodiments, R⁴ is-DRIIDS*GLDS*M (SEQ ID NO:5). In embodiments, R⁴ is -G₀₋₁₀DRIIDS*GLDS*M(SEQ NO:6) or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein S* is aphosphoserine. In embodiments, R⁴ is -G₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6).“IκBα” is used in accordance with its well understood meaning and refersto a protein that inhibits NF-κB transcription factor. In embodiments,phosphopeptide including a sequence of IκBα is as described in P. NatlAcad Sci USA (2001) July 17, vol. 98(15) 8554-8559. In embodiments, R⁴includes a phosphopeptide including a sequence of IκBα, or an analog,derivative, or prodrug thereof. In embodiments, R⁴ includes aphosphopeptide consisting of a sequence of IκBα, or an analog,derivative, or prodrug thereof. In embodiments, R⁴ includes-RAEDS*GNES*EGE (SEQ ID NO:3) or a derivative thereof (e.g., includingone, two or three substitutions (e.g., conservative substitutions),wherein S* is a phosphoserine. In embodiments, R⁴ includes-RAEDS*GNES*EGE (SEQ ID NO:3). In embodiments, R⁴ is G₀₋₁₀RAEDS*GNES*EGE(SEQ ID NO:4) or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein S* is aphosphoserine. In embodiments, R⁴ includes -G₀₋₁₀RAEDS*GNES*EGE (SEQ IDNO:4). In embodiments, R⁴ includes -DRIIDS*GLDS*M (SEQ ID NO:5) or aderivative thereof (e.g., including one, two or three substitutions(e.g., conservative substitutions), wherein S* is a phosphoserine. Inembodiments, R⁴ includes -DRIIDS*GLDS*M (SEQ ID NO:5). In embodiments,R⁴ includes -G₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6) or a derivative thereof(e.g., including one, two or three substitutions (e.g., conservativesubstitutions), wherein S* is a phosphoserine. In embodiments, R⁴includes -G₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6).

In embodiments, R⁴ is a nutlin moiety or an analog, derivative, orprodrug thereof. In embodiments, R⁴ is a nutlin-3 moiety or an analog,derivative, or prodrug thereof. In embodiments, R⁴ is a(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-11-carbonyl]-piperazin-2-one moiety. In embodiments, R⁴ is a(−)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁴ is a(+)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁴ is a nutlin moiety. In embodiments, R⁴ is anutlin-3 moiety. “Nutlin” and “nutlin-3” are used in accordance withtheir well understood meaning and refer to cis-imidazoline analogs. Inembodiments, nutlin or nutlin-3 is as described in Bioorg. Med. Chem.Lett (2008) 18 5904-5908. In embodiments, R⁴ includes a nutlin moiety oran analog, derivative, or prodrug thereof. In embodiments, R⁴ includes anutlin-3 moiety or an analog, derivative, or prodrug thereof. Inembodiments, R⁴ includes a(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁴ includes a(−)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁴ includes a(+)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁴ includes a nutlin moiety.

In embodiments, R⁴ is a hydroxyproline containing HIF-1α pentapeptidemoiety or an analog, derivative, or prodrug thereof. In embodiments, R⁴is -LAP*YI or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein P* is ahydroxyproline. In embodiments, R⁴ is -G₀₋₁₀LAP*YI or a derivativethereof (e.g., including one, two or three substitutions (e.g.,conservative substitutions), wherein P* is a hydroxyproline. Inembodiments, R⁴ is -LAP*YI. In embodiments, R⁴ is -G₀₋₁₀LAP*YI. “HIF-1α”is used in accordance with its well understood meaning and refers to thehypoxia-inducible factor 1-alpha transcription factor. In embodiments,HIF-1α is as described in Oncogene (2008) 27, 7201-7211. In embodiments,R⁴ includes a hydroxyproline containing HIF-1α pentapeptide moiety or ananalog, derivative, or prodrug thereof. In embodiments, R⁴ includes-LAP*YI or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein P* is ahydroxyproline. In embodiments, R⁴ includes -G₀₋₁₀LAP*YI or a derivativethereof (e.g., including one, two or three substitutions (e.g.,conservative substitutions), wherein P* is a hydroxyproline. Inembodiments, R⁴ includes -LAP*YI. In embodiments, R⁴ includes-G₀₋₁₀LAP*YI.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a thalidomide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a thalidomide moiety. In embodiments of a derivative, anoriginal substituent (e.g., substituent group) of a thalidomide moietyis replaced with an alternative substituent (e.g., substituent group),wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of a thalidomide moiety are replaced with aplurality of alternative substituents (e.g., substituent groups),wherein the alternative substituents (e.g., substituent groups) are eachoptionally different and each alternative substituent (e.g., substituentgroup) is different from the original substituent (e.g., substituentgroup) it replaces. In embodiments of a derivative, a hydrogen atom of athalidomide moiety is replaced with a substituent (e.g., substituentgroup). In embodiments of a derivative, a plurality of hydrogen atoms ofa thalidomide moiety are replaced with a plurality of substituents(e.g., substituent groups), wherein the substituents (e.g., substituentgroups) are each optionally different.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a phthalimide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a phthalimide moiety. In embodiments of a derivative, anoriginal substituent (e.g., substituent group) of a phthalimide moietyis replaced with an alternative substituent (e.g., substituent group),wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of a phthalimide moiety are replaced with aplurality of alternative substituents (e.g., substituent groups),wherein the alternative substituents (e.g., substituent groups) are eachoptionally different and each alternative substituent (e.g., substituentgroup) is different from the original substituent (e.g., substituentgroup) it replaces. In embodiments of a derivative, a hydrogen atom of aphthalimide moiety is replaced with a substituent (e.g., substituentgroup). In embodiments of a derivative, a plurality of hydrogen atoms ofa phthalimide moiety are replaced with a plurality of substituents(e.g., substituent groups), wherein the substituents (e.g., substituentgroups) are each optionally different.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is adamantyl or a derivative, analog,or prodrug thereof. In embodiments, the degradation-increasing moiety isan analog thereof. In embodiments, the degradation-increasing moiety isa derivative thereof. In embodiments, the degradation-increasing moietyis a prodrug thereof (e.g., a physiologically hydrolyzable ester thereofor a physiologically hydrolyzable amide thereof). In embodiments, thedegradation-increasing moiety is adamantyl. In embodiments of aderivative, an original substituent (e.g., substituent group) ofadamantyl is replaced with an alternative substituent (e.g., substituentgroup), wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of adamantyl are replaced with a plurality ofalternative substituents (e.g., substituent groups), wherein thealternative substituents (e.g., substituent groups) are each optionallydifferent and each alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group) itreplaces. In embodiments of a derivative, a hydrogen atom of adamantylis replaced with a substituent (e.g., substituent group). In embodimentsof a derivative, a plurality of hydrogen atoms of adamantyl are replacedwith a plurality of substituents (e.g., substituent groups), wherein thesubstituents (e.g., substituent groups) are each optionally different.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is an IκBα phosphopeptide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is an IκBα phosphopeptide moiety. In embodiments of a derivative,an original substituent (e.g., substituent group) of an IκBαphosphopeptide moiety is replaced with an alternative substituent (e.g.,substituent group), wherein the alternative substituent (e.g.,substituent group) is different from the original substituent (e.g.,substituent group). In embodiments of a derivative, a plurality oforiginal substituents (e.g., substituent groups) of an IκBαphosphopeptide moiety are replaced with a plurality of alternativesubstituents (e.g., substituent groups), wherein the alternativesubstituents (e.g., substituent groups) are each optionally differentand each alternative substituent (e.g., substituent group) is differentfrom the original substituent (e.g., substituent group) it replaces. Inembodiments of a derivative, a hydrogen atom of an IκBα phosphopeptidemoiety is replaced with a substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of hydrogen atoms of an IκBαphosphopeptide moiety are replaced with a plurality of substituents(e.g., substituent groups), wherein the substituents (e.g., substituentgroups) are each optionally different.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a nutlin moiety or a derivative,analog, or prodrug thereof. In embodiments, the degradation-increasingmoiety is an analog thereof. In embodiments, the degradation-increasingmoiety is a derivative thereof. In embodiments, thedegradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a nutlin moiety. In embodiments of a derivative, an originalsubstituent (e.g., substituent group) of a nutlin moiety is replacedwith an alternative substituent (e.g., substituent group), wherein thealternative substituent (e.g., substituent group) is different from theoriginal substituent (e.g., substituent group). In embodiments of aderivative, a plurality of original substituents (e.g., substituentgroups) of a nutlin moiety are replaced with a plurality of alternativesubstituents (e.g., substituent groups), wherein the alternativesubstituents (e.g., substituent groups) are each optionally differentand each alternative substituent (e.g., substituent group) is differentfrom the original substituent (e.g., substituent group) it replaces. Inembodiments of a derivative, a hydrogen atom of a nutlin moiety isreplaced with a substituent (e.g., substituent group). In embodiments ofa derivative, a plurality of hydrogen atoms of a nutlin moiety arereplaced with a plurality of substituents (e.g., substituent groups),wherein the substituents (e.g., substituent groups) are each optionallydifferent.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a HIF-1α pentapeptide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a HIF-1α pentapeptide moiety. In embodiments of a derivative,an original substituent (e.g., substituent group) of a HIF-1αpentapeptide moiety is replaced with an alternative substituent (e.g.,substituent group), wherein the alternative substituent (e.g.,substituent group) is different from the original substituent (e.g.,substituent group). In embodiments of a derivative, a plurality oforiginal substituents substituent groups) of a HIF-1α pentapeptidemoiety are replaced with a plurality of alternative substituents (e.g.,substituent groups), wherein the alternative substituents (e.g.,substituent groups) are each optionally different and each alternativesubstituent (e.g., substituent group) is different from the originalsubstituent (e.g., substituent group) it replaces. In embodiments of aderivative, a hydrogen atom of a HIF-1α pentapeptide moiety is replacedwith a substituent (e.g., substituent group). In embodiments of aderivative, a plurality of hydrogen atoms of a HIF-1α pentapeptidemoiety are replaced with a plurality of substituents (e.g., substituentgroups), wherein the substituents (e.g., substituent groups) are eachoptionally different.

In embodiments, R⁴ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is

or a derivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is

In embodiments of a derivative, an original substituent (e.g.,substituent group) of

is replaced with an alternative substituent (e.g., substituent group),wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of

are replaced with a plurality of alternative substituents (e.g.,substituent groups), wherein the alternative substituents (e.g.,substituent groups) are each optionally different and each alternativesubstituent (e.g., substituent group) is different from the originalsubstituent (e.g., substituent group) it replaces. In embodiments of aderivative, a hydrogen atom of

is replaced with a substituent (e.g., substituent group). In embodimentsof a derivative, a plurality of hydrogen atoms of

are replaced with a plurality of substituents (e.g., substituentgroups), wherein the substituents substituent groups) are eachoptionally different.

In embodiments, R⁵ is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R⁵ is independently halogen, —CF₃, —CHF₂, —OCF₃, —OCHF₂,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2to 8 membered heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R⁵ is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁵ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R⁵ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R⁵ is independently halogen. In embodiments, R⁵is independently —CF₃. In embodiments, R⁵ is independently —CHF₂. Inembodiments, R⁵ is independently —CH₂F. In embodiments, R⁵ isindependently —OCF₃. In embodiments, R⁵ is independently —OCHF₂. Inembodiments, R⁵ is independently —OCH₂F. In embodiments, R⁵ isindependently substituted or unsubstituted C₁-C₈ alkyl. In embodiments,R⁵ is independently substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, R⁵ is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁵ is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R⁵ is independently substituted or unsubstituted 5to 10 membered heteroaryl. In embodiments, R⁵ is independently —OH. Inembodiments, R⁵ is independently —NH₂. In embodiments, R⁵ isindependently —SH. In embodiments, R⁵ is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R⁵ is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R⁵ is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R⁵ is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R⁵ isindependently substituted or unsubstituted phenyl. In embodiments, R⁵ isindependently substituted or unsubstituted 5 to 6 membered heteroaryl.In embodiments, R⁵ is independently substituted C₁-C₈ alkyl. Inembodiments, R⁵ is independently substituted 2 to 8 memberedheteroalkyl. In embodiments, R⁵ is independently substituted C₃-C₈cycloalkyl. In embodiments, R⁵ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R⁵ is independentlysubstituted C₆-C₁₀ aryl. In embodiments, R⁵ is independently substituted5 to 10 membered heteroaryl. In embodiments, R⁵ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R⁵ is independently substitutedto 4 membered heteroalkyl. In embodiments, R⁵ is independentlysubstituted C₃-C₆ cycloalkyl. In embodiments, R⁵ is independentlysubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R⁵ isindependently substituted phenyl. In embodiments, R⁵ is independentlysubstituted 5 to 6 membered heteroaryl. In embodiments, R⁵ isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R⁵ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R⁵ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R⁵is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁵ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R⁵ is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R⁵ is independently unsubstituted C₁-C₄alkyl. In embodiments, R⁵ is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R⁵ is independently unsubstituted C₃-C₆cycloalkyl. In embodiments, R⁵ is independently unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R⁵ is independentlyunsubstituted phenyl. In embodiments, R⁵ is independently unsubstituted5 to 6 membered heteroaryl. In embodiments, R⁵ is —NH₂.

In embodiments, -L⁵-R⁵ is unsubstituted methoxy.

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is substituted or unsubstituted 5 to 10 memberedheteroalkyl. In embodiments, -L⁵-R⁵ is substituted or unsubstituted 6 to10 membered heteroalkyl. In embodiments, -L⁵-R⁵ is substituted orunsubstituted 7 to 10 membered heteroalkyl. In embodiments, -L⁵-R⁵ issubstituted or unsubstituted 7 to 9 membered heteroalkyl. Inembodiments, -L⁵-R⁵ is substituted or unsubstituted 5 memberedheteroaryl. In embodiments, -L⁵-R⁵ is substituted or unsubstituted 5 to6 membered heteroaryl. In embodiments, -L⁵-R⁵ is substituted orunsubstituted 4 to 6 membered heteroaryl. In embodiments, -L⁵-R⁵ issubstituted or unsubstituted heteroaryl. In embodiments, -L⁵-R⁵ issubstituted 5 membered heteroaryl. In embodiments, -L⁵-R⁵ is substituted5 to 6 membered heteroaryl. In embodiments, -L⁵-R⁵ is substituted 4 to 6membered heteroaryl. In embodiments, -L⁵-R⁵ is substituted heteroaryl.In embodiments, -L⁵-R⁵ is unsubstituted 5 membered heteroaryl. Inembodiments, -L⁵-R⁵ is unsubstituted 5 to 6 membered heteroaryl. Inembodiments, -L⁵-R⁵ is unsubstituted heteroaryl. In embodiments, -L⁵-R⁵is unsubstituted 4 to 6 membered heteroaryl.

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is

In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety. In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety. In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety. In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety. In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety. In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety. In embodiments, -L⁵-R⁵ is

when R⁴ is a degradation-increasing moiety.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is thalidomide moiety or an analog,derivative, or prodrug thereof; phthalimide moiety or an analog,derivative, or prodrug thereof; adamantyl or an analog, derivative, orprodrug thereof; an IκBα phosphopeptide moiety or an analog, derivative,or prodrug thereof; nutlin moiety or an analog, derivative, or prodrugthereof; HIF-1α pentapeptide moiety or an analog, derivative, or prodrugthereof; or

or an analog, derivative, or prodrug thereof. In embodiments, thedegradation-increasing moiety is thalidomide moiety or an analog,derivative, or prodrug thereof. In embodiments, R⁵ is

or an analog, derivative, or prodrug thereof. In embodiments, R⁵ is

In embodiments, R⁵ is a thalidomide moiety or an analog, derivative, orprodrug thereof. In embodiments, R⁵ is a thalidomide moiety. Inembodiments, R⁵ is a lenalidomide moiety. In embodiments, R⁵ is apomalidomide moiety. In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is a phthalimide moiety or an analog, derivative, orprodrug thereof. In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is a phthalimide moiety. In embodiments, R⁵ includesa thalidomide moiety or an analog, derivative, or prodrug thereof. Inembodiments, R⁵ includes a thalidomide moiety. In embodiments, R⁵includes a lenalidomide moiety. In embodiments, R⁵ includes apomalidomide moiety. In embodiments, R⁵ includes a phthalimide moiety oran analog, derivative, or prodrug thereof. In embodiments, R⁵ includes aphthalimide moiety.

In embodiments, R⁵ is adamantyl or an analog, derivative, or prodrugthereof. In embodiments, R⁵ is substituted adamantyl or an analog,derivative, or prodrug thereof. In embodiments, R⁵ is adamantyl. Inembodiments, R⁵ is substituted adamantyl. In embodiments, R⁵ isadamantyl. In embodiments, R⁵ is substituted adamantyl.

In embodiments, R⁵ is a phosphopeptide consisting of a sequence of IκBα,or an analog, derivative, or prodrug thereof. In embodiments, R⁵ is-RAEDS*GNES*EGE (SEQ ID NO:3) or a derivative thereof (e.g., includingone, two or three substitutions (e.g., conservative substitutions),wherein S* is a phosphoserine. In embodiments, R⁵ is -RAEDS*GNES*EGE(SEQ ID NO:3). In embodiments, R⁵ is -G₀₋₁₀RAEDS*GNES*EGE (SEQ ID NO:4)or a derivative thereof (e.g., including one, two or three substitutions(e.g., conservative substitutions), wherein S* is a phosphoserine. Inembodiments, R⁵ is G₀₋₁₀RAEDS*GNES*EGE (SEQ ID NO:4). In embodiments, R⁵is -DRIIDS*GLDS*M (SEQ ID NO:5) or a derivative thereof (e.g., includingone, two or three substitutions (e.g., conservative substitutions),wherein S* is a phosphoserine. In embodiments, R⁵ is -DRIIDS*GLDS*M (SEQID NO:5). In embodiments, R⁵ is G₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6) or aderivative thereof (e.g., including one, two or three substitutions(e.g., conservative substitutions), wherein S* is a phosphoserine. Inembodiments, R⁵ is -G₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6). “IκBα” is used inaccordance with its well understood meaning and refers to a protein thatinhibits NF-κB transcription factor. In embodiments, phosphopeptideincluding a sequence of IκBα is as described in P. Natl Acad Sci USA(2001) July 17, vol. 98(15) 8554-8559. In embodiments, R⁵ includes aphosphopeptide including a sequence of IκBα, or an analog, derivative,or prodrug thereof. In embodiments, R⁵ includes a phosphopeptideconsisting of a sequence of IκBα, or an analog, derivative, or prodrugthereof. In embodiments, R⁵ includes -RAEDS*GNES*EGE (SEQ ID NO:3) or aderivative thereof (e.g., including one, two or three substitutions(e.g., conservative substitutions), wherein S* is a phosphoserine. Inembodiments, R⁵ includes -RAEDS*GNES*EGE (SEQ ID NO:3). In embodiments,R⁵ is -G₀₋₁₀RAEDS*GNES*EGE (SEQ ID NO:4) or a derivative thereof (e.g.,including one, two or three substitutions (e.g., conservativesubstitutions), wherein S* is a phosphoserine. In embodiments, R⁵includes -G₀₋₁₀RAEDS*GNES*EGE (SEQ ID NO:4). In embodiments, R⁵ includes-DRIIDS*GLDS*M (SEQ ID NO:5) or a derivative thereof (e.g., includingone, two or three substitutions (e.g., conservative substitutions),wherein S* is a phosphoserine. In embodiments, R⁵ includes-DRIIDS*GLDS*M (SEQ NO:5). In embodiments, R⁵ includesG₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6) or a derivative thereof (e.g.,including one, two or three substitutions (e.g., conservativesubstitutions), wherein S* is a phosphoserine. In embodiments, R⁵includes -G₀₋₁₀DRIIDS*GLDS*M (SEQ ID NO:6).

In embodiments, R⁵ is a nutlin moiety or an analog, derivative, orprodrug thereof. In embodiments, R⁵ is a nutlin-3 moiety or an analog,derivative, or prodrug thereof. In embodiments, R⁵ is a(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁵ is a(−)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁵ is a(+)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁵ is a nutlin moiety. In embodiments, R⁵ is anutlin-3 moiety. “Nutlin” and “nutlin-3” are used in accordance withtheir well understood meaning and refer to cis-imidazoline analogs. Inembodiments, nutlin or nutlin-3 is as described in Bioorg. Med. Chem.Lett (2008) 18 5904-5908. In embodiments, R⁵ includes a nutlin moiety oran analog, derivative, or prodrug thereof. In embodiments, R⁵ includes anutlin-3 moiety or an analog, derivative, or prodrug thereof. Inembodiments, R⁵ includes a(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁵ includes a(−)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁵ includes a(+)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-onemoiety. In embodiments, R⁵ includes a nutlin moiety.

In embodiments, R⁵ is a hydroxyproline containing HIF-1α pentapeptidemoiety or an analog, derivative, or prodrug thereof. In embodiments, R⁵is -LAP*YI or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein P* is ahydroxyproline. In embodiments, R⁵ is -LAP*YI. In embodiments, R⁵ is-G₀₋₁₀LAP*YI or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein P* is ahydroxyproline. In embodiments, R⁵ is -G₀₋₁₀LAP*YI. “HIF-1α” is used inaccordance with its well understood meaning and refers to thehypoxia-inducible factor 1-alpha transcription factor. In embodiments,HIF-1α is as described in Oncogene (2008) 27, 7201-7211. In embodiments,R⁵ includes a hydroxyproline containing HIF-1α pentapeptide moiety or ananalog, derivative, or prodrug thereof. In embodiments, R⁵ includes-LAP*YI or a derivative thereof (e.g., including one, two or threesubstitutions (e.g., conservative substitutions), wherein P* is ahydroxyproline. In embodiments, R⁵ includes -G₀₋₁₀LAP*YI or a derivativethereof (e.g., including one, two or three substitutions (e.g.,conservative substitutions), wherein P* is a hydroxyproline. Inembodiments, R⁵ includes -LAP*YI. In embodiments, R⁵ includes-G₀₋₁₀LAP*YI.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a thalidomide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof in embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a thalidomide moiety. In embodiments of a derivative, anoriginal substituent (e.g., substituent group) of a thalidomide moietyis replaced with an alternative substituent (e.g., substituent group),wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of a thalidomide moiety are replaced with aplurality of alternative substituents (e.g., substituent groups),wherein the alternative substituents (e.g., substituent groups) are eachoptionally different and each alternative substituent (e.g., substituentgroup) is different from the original substituent (e.g., substituentgroup) it replaces. In embodiments of a derivative, a hydrogen atom of athalidomide moiety is replaced with a substituent (e.g., substituentgroup). In embodiments of a derivative, a plurality of hydrogen atoms ofa thalidomide moiety are replaced with a plurality of substituents(e.g., substituent groups), wherein the substituents (e.g., substituentgroups) are each optionally different.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a phthalimide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a phthalimide moiety. In embodiments of a derivative, anoriginal substituent (e.g., substituent group) of a phthalimide moietyis replaced with an alternative substituent (e.g., substituent group),wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of a phthalimide moiety are replaced with aplurality of alternative substituents (e.g., substituent groups),wherein the alternative substituents (e.g., substituent groups) are eachoptionally different and each alternative substituent (e.g., substituentgroup) is different from the original substituent (e.g., substituentgroup) it replaces. In embodiments of a derivative, a hydrogen atom of aphthalimide moiety is replaced with a substituent (e.g., substituentgroup). In embodiments of a derivative, a plurality of hydrogen atoms ofa phthalimide moiety are replaced with a plurality of substituents(e.g., substituent groups), wherein the substituents (e.g., substituentgroups) are each optionally different.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is adamantyl or a derivative, analog,or prodrug thereof. In embodiments, the degradation-increasing moiety isan analog thereof. In embodiments, the degradation-increasing moiety isa derivative thereof. In embodiments, the degradation-increasing moietyis a prodrug thereof (e.g., a physiologically hydrolyzable ester thereofor a physiologically hydrolyzable amide thereof). In embodiments, thedegradation-increasing moiety is adamantyl. In embodiments of aderivative, an original substituent (e.g., substituent group) ofadamantyl is replaced with an alternative substituent (e.g., substituentgroup), wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of adamantyl are replaced with a plurality ofalternative substituents (e.g., substituent groups), wherein thealternative substituents (e.g., substituent groups) are each optionallydifferent and each alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group) itreplaces. In embodiments of a derivative, a hydrogen atom of adamantylis replaced with a substituent (e.g., substituent group). In embodimentsof a derivative, a plurality of hydrogen atoms of adamantyl are replacedwith a plurality of substituents (e.g., substituent groups), wherein thesubstituents (e.g., substituent groups) are each optionally different.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is an IκBα phosphopeptide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is an IκBα phosphopeptide moiety. In embodiments of a derivative,an original substituent (e.g., substituent group) of an IκBαphosphopeptide moiety is replaced with an alternative substituent (e.g.,substituent group), wherein the alternative substituent (e.g.,substituent group) is different from the original substituent (e.g.,substituent group). In embodiments of a derivative, a plurality oforiginal substituents (e.g., substituent groups) of an IκBαphosphopeptide moiety are replaced with a plurality of alternativesubstituents (e.g., substituent groups), wherein the alternativesubstituents (e.g., substituent groups) are each optionally differentand each alternative substituent (e.g., substituent group) is differentfrom the original substituent (e.g., substituent group) it replaces. Inembodiments of a derivative, a hydrogen atom of an IκBα phosphopeptidemoiety is replaced with a substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of hydrogen atoms of an IκBαphosphopeptide moiety are replaced with a plurality of substituents(e.g., substituent groups), wherein the substituents (e.g., substituentgroups) are each optionally different.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a nutlin moiety or a derivative,analog, or prodrug thereof. In embodiments, the degradation-increasingmoiety is an analog thereof. In embodiments, the degradation-increasingmoiety is a derivative thereof. In embodiments, thedegradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a nutlin moiety. In embodiments of a derivative, an originalsubstituent (e.g., substituent group) of a nutlin moiety is replacedwith an alternative substituent (e.g., substituent group), wherein thealternative substituent (e.g., substituent group) is different from theoriginal substituent (e.g., substituent group). In embodiments of aderivative, a plurality of original substituents (e.g., substituentgroups) of a nutlin moiety are replaced with a plurality of alternativesubstituents (e.g., substituent groups), wherein the alternativesubstituents (e.g., substituent groups) are each optionally differentand each alternative substituent (e.g., substituent group) is differentfrom the original substituent (e.g., substituent group) it replaces. Inembodiments of a derivative, a hydrogen atom of a nutlin moiety isreplaced with a substituent (e.g., substituent group). In embodiments ofa derivative, a plurality of hydrogen atoms of a nutlin moiety arereplaced with a plurality of substituents (e.g., substituent groups),wherein the substituents (e.g., substituent groups) are each optionallydifferent.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is a HIF-1α pentapeptide moiety or aderivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is a HIF-1α pentapeptide moiety. In embodiments of a derivative,an original substituent (e.g., substituent group) of a HIF-1αpentapeptide moiety is replaced with an alternative substituent (e.g.,substituent group), wherein the alternative substituent (e.g.,substituent group) is different from the original substituent (e.g.,substituent group). In embodiments of a derivative, a plurality oforiginal substituents substituent groups) of a HIF-1α pentapeptidemoiety are replaced with a plurality of alternative substituents (e.g.,substituent groups), wherein the alternative substituents (e.g.,substituent groups) are each optionally different and each alternativesubstituent (e.g., substituent group) is different from the originalsubstituent (e.g., substituent group) it replaces. In embodiments of aderivative, a hydrogen atom of a HIF-1α pentapeptide moiety is replacedwith a substituent (e.g., substituent group). In embodiments of aderivative, a plurality of hydrogen atoms of a HIF-1α pentapeptidemoiety are replaced with a plurality of substituents (e.g., substituentgroups), wherein the substituents (e.g., substituent groups) are eachoptionally different.

In embodiments, R⁵ is a degradation-increasing moiety. In embodiments,the degradation-increasing moiety is

or a derivative, analog, or prodrug thereof. In embodiments, thedegradation-increasing moiety is an analog thereof. In embodiments, thedegradation-increasing moiety is a derivative thereof. In embodiments,the degradation-increasing moiety is a prodrug thereof (e.g., aphysiologically hydrolyzable ester thereof or a physiologicallyhydrolyzable amide thereof). In embodiments, the degradation-increasingmoiety is

In embodiments of a derivative, an original substituent (e.g.,substituent group) of

is replaced with an alternative substituent (e.g., substituent group),wherein the alternative substituent (e.g., substituent group) isdifferent from the original substituent (e.g., substituent group). Inembodiments of a derivative, a plurality of original substituents (e.g.,substituent groups) of

are replaced with a plurality of alternative substituents (e.g.,substituent groups), wherein the alternative substituents (e.g.,substituent groups) are each optionally different and each alternativesubstituent (e.g., substituent group) is different from the originalsubstituent (e.g., substituent group) it replaces. In embodiments of aderivative, a hydrogen atom of

is replaced with a substituent (e.g., substituent group). In embodimentsof a derivative, a plurality of hydrogen atoms of

are replaced with a plurality of substituents (e.g., substituentgroups), wherein the substituents substituent groups) are eachoptionally different.

In embodiments, R⁶ is independently a hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, orsubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R⁶ is —CN. In embodiments, R⁶ is independently a hydrogen.

In embodiments, W¹ is N. In embodiments, W¹ is C(R⁶).

In embodiments, L¹ is a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—,—C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted or unsubstituted C₁-C₃alkylene or substituted or unsubstituted 2 to 3 membered heteroalkylene.In embodiments, L¹ is —O—, substituted or unsubstituted C₁-C₃ alkyleneor substituted or unsubstituted 2 to 3 membered heteroalkylene. Inembodiments, L¹ is —O—. In embodiments, L¹ is a bond. In embodiments, L¹is —OCH₂—. In embodiments, L¹ is —CH₂O—.

In embodiments, L² is a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—,—C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted or unsubstituted C₁-C₃alkylene or substituted or unsubstituted 2 to 3 membered heteroalkylene.In embodiments, L² is a bond. In embodiments, L² is —C(O)NH—. Inembodiments, L² is —NHC(O)—. In embodiments, L² is —NHC(O)NH—. Inembodiments, L² is —OCH₂—. In embodiments, L² is —CH₂O—.

In embodiments, the linker (e.g., linker that forms a divalent linkersuch as L⁴ and/or L⁵) is a polyethylene glycol linker. In embodiments,the linker (e.g., linker that forms a divalent linker such as L⁴ and/orL⁵) is hydrophilic. In embodiments, the linker (e.g., linker that formsa divalent linker such as L⁴ and/or L⁵) is hydrophobic. In embodiments,the linker (e.g., linker that forms a divalent linker such as L⁴ and/orL⁵) includes a disulfide bond. In embodiments, the linker (e.g., linkerthat forms a divalent linker such as L⁴ and/or L⁵) includes a hydrazonebond. In embodiments, the linker (e.g., linker that forms a divalentlinker such as L⁴ and/or L⁵) includes an ester. In embodiments, thelinker (e.g., linker that forms a divalent linker such as L⁴ and/or L⁵)includes a sulfonyl. In embodiments, the linker (e.g., linker that formsa divalent linker such as L⁴ and/or L⁵) includes a thioether. Inembodiments, the linker (e.g., linker that forms a divalent linker suchas L⁴ and/or L⁵) includes an ether. In embodiments, the linker (e.g.,linker that forms a divalent linker such as L⁴ and/or L⁵) includes aphosphinate. In embodiments, the linker (e.g., linker that forms adivalent linker such as L⁴ and/or L⁵) includes an alkyloxime bond. Inembodiments, the linker (e.g., linker that forms a divalent linker suchas L⁴ and/or L⁵) includes one or more amino acids. In embodiments, thelinker (e.g., linker that forms a divalent linker such as L⁴ and/or L⁵)consists of amino acids. In embodiments, the linker (e.g., linker thatforms a divalent linker such as L⁴ and/or L⁵) includes amino acidderivatives. In embodiments, the linker (e.g., linker that forms adivalent linker such as L⁴ and/or L⁵) is a linker as described inBioconjugate Techniques (Second Edition) by Greg T. Hermanson (2008),which is herein incorporated by referenced in its entirety for allpurposes. In embodiments, the linker (e.g., linker that forms a divalentlinker such as L⁴ and/or L⁵) is a linker as described in Flygare J A,Pillow T H, Aristoff P., Antibody-drug conjugates for the treatment ofcancer. Chemical Biology and Drug Design. 2013 January; 81(1):113-21,which is herein incorporated by referenced in its entirety for allpurposes. In embodiments, the linker (e.g., linker that forms a divalentlinker such as L⁴ and/or L⁵) is a linker as described in Drachman J G,Senter P D., Antibody-drug conjugates: the chemistry behind empoweringantibodies to fight cancer. Hematology Am Soc Hematol Educ Program.2013; 2013:306-10, which is herein incorporated by referenced in itsentirety for all purposes. In embodiments, L⁴ and/or L⁵ are linkersresulting from bioconjugate chemistry as disclosed herein.

In embodiments, L⁴ is L^(4A)-L^(4B)-L^(4C) and L^(4A), L^(4B), andL^(4C) are each independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L⁴ is abond, —NH—, —S—, —O—, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L⁴ is substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L⁴ isL^(4A)-L^(4B)-L^(4C). In embodiments, L^(4A) is a bond, —NH—, —S—, —O—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. In embodiments,L^(4B) is a bond, —NH—, —S—, —O—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L^(4C) is abond, —NH—, —S—, —O—, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L^(4A) is substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L^(4B) is abond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L^(4C) is a bond, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

In embodiments, L^(4A) is substituted or unsubstituted C₁-C₂₀ alkylene,substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L^(4A) is substituted orunsubstituted 3 to 8 membered heteroalkylene. In embodiments, L^(4A) is—CH₂CH₂OCH₂—. In embodiments, L^(4A) is unsubstituted 3 to 8 memberedheteroalkylene. In embodiments, L^(4A) is unsubstituted 3 to 6 memberedheteroalkylene. In embodiments, L^(4A) is unsubstituted 3 to 5 memberedheteroalkylene. In embodiments, L^(4A) is a bond.

In embodiments, L^(4B) is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L^(4B) is a substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, L^(4B) isa bond. In embodiments, L^(4B) is a substituted or unsubstituted 5 to 6membered heteroarylene. In embodiments, L^(4B) is an unsubstituted 5 to6 membered heteroarylene. In embodiments, L^(4B) is unsubstituteddivalent triazole. In embodiments, L^(4B) is unsubstituted divalent1H-1,2,3-triazole. In embodiments, L^(4B) is unsubstituted divalent2H-1,2,3-triazole. In embodiments, L^(4B) is unsubstituted divalentfuran.

In embodiments, L^(4C) is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L^(4C) is a substituted orunsubstituted 2 to 12 membered heteroalkylene. In embodiments, L^(4C) isa substituted or unsubstituted 2 to 32 membered heteroalkylene. Inembodiments, L^(4C) is a bond.

In embodiments, L^(4C) is a divalent oligomer of ethylene oxide. Inembodiments, L^(4C) is a divalent polyethylene glycol. In embodiments,L^(4C) is a divalent oligomer of ethylene oxide having 2 to 30 linearatoms (carbon and oxygen) between the two termini connecting to theremainder of the compound. In embodiments, L^(4C) is—(CH₂CH₂O)_(x)CH₂CH₂— and x is an integer from 1 to 16. In embodiments,x is an integer from 2 to 15. In embodiments, x is an integer from 3 to14. In embodiments, x is an integer from 4 to 12. In embodiments, x isan integer from 5 to 10. In embodiments, x is an integer from 5 to 8. Inembodiments, x is an integer from 6 to 7.

In embodiments, L⁵ is L^(5A)-L^(5B)-L^(5C) and L^(5A), L^(5B), andL^(5C) are each independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L⁵ is abond, —NH—, —S—, —O—, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L⁵ is substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L⁵ isL^(5A)-L^(5B)-L^(5C). In embodiments, L^(5A) is a bond, —NH—, —S—, —O—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. In embodiments,L^(5B) is a bond, —NH—, —S—, —O—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L^(5C) is abond, —NH—, —S—, —O—, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L^(5A) is substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L^(5B) is abond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylenesubstituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L^(5C) is a bond, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

In embodiments, L^(5A) is substituted or unsubstituted C₁-C₂₀ alkylene,substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L^(5A) is substituted orunsubstituted 3 to 8 membered heteroalkylene. In embodiments, L^(5A) is—CH₂CH₂OCH₂—. In embodiments, L^(5A) is unsubstituted 3 to 8 memberedheteroalkylene. In embodiments, L^(5A) is unsubstituted 3 to 6 memberedheteroalkylene. In embodiments, L^(5A) is unsubstituted 3 to 5 memberedheteroalkylene. In embodiments, L^(5A) is a bond.

In embodiments, L^(5B) is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L^(5B) is a substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, L^(5B) isa bond. In embodiments, L^(5B) is a substituted or unsubstituted 5 to 6membered heteroarylene. In embodiments, L^(5B) is an unsubstituted 5 to6 membered heteroarylene. In embodiments, L^(5B) is unsubstituteddivalent triazole. In embodiments, L^(5B) is unsubstituted divalent1H-1,2,3-triazole. In embodiments, L^(5B) is unsubstituted divalent2H-1,2,3-triazole.

In embodiments, L^(5C) is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L^(5C) is a substituted orunsubstituted 2 to 12 membered heteroalkylene. In embodiments, L^(5C) isa substituted or unsubstituted 2 to 32 membered heteroalkylene. Inembodiments, L^(5C) is a bond.

In embodiments, L^(5C) is a divalent oligomer of ethylene oxide. Inembodiments, L^(5C) is a divalent polyethylene glycol. In embodiments,L^(5C) is a divalent oligomer of ethylene oxide having 2 to 30 linearatoms (carbon and oxygen) between the two termini connecting to theremainder of the compound. In embodiments, L^(5C) is—(CH₂CH₂O)_(x)CH₂CH₂— and x is an integer from 1 to 16. In embodiments,x is an integer from 2 to 15. In embodiments, x is an integer from 3 to14. In embodiments, x is an integer from 4 to 12. In embodiments, x isan integer from 5 to 10. In embodiments, x is an integer from 5 to 8. Inembodiments, x is an integer from 6 to 7.

Conjugates described herein may be synthesized using bioconjugate orconjugate chemistry. Conjugate chemistry includes coupling two moleculestogether to form an adduct. Conjugation may be a covalent modification.Currently favored classes of conjugate chemistry reactions availablewith reactive known reactive groups are those which proceed underrelatively mild conditions. These include, but are not limited tonucleophilic substitutions (e.g., reactions of amines and alcohols witharyl halides, active esters), electrophilic substitutions (e.g., enaminereactions) and additions to carbon-carbon and carbon-heteroatom multiplebonds (e.g., Michael reaction, Diels-Alder addition). These and otheruseful reactions are discussed in, for example, March, ADVANCED ORGANICCHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney etal., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198,American Chemical Society, Washington, D.C., 1982. In embodiments, thebioconjugation reaction is a click chemistry reaction (Angewandte ChemieInternational Edition 40 (11): 2004-2021). In embodiments, thebioconjugation reaction is a Huisgen cyclization of azides. Inembodiments, the bioconjugation reaction is a copper catalyzed Huisgencyclization of azides.

Useful reactive functional groups used for conjugate chemistries hereininclude, for example:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxysuccinimide esters,        N-hydroxybenztriazole esters, acid halides, acyl imidazoles,        thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and        aromatic esters;    -   (b) hydroxyl groups which can be converted to esters, ethers,        aldehydes, etc.    -   (c) haloalkyl groups wherein the halide can be later displaced        with a nucleophilic group such as, for example, an amine, a        carboxylate action, thiol anion, carbanion, or an alkoxide ion,        thereby resulting in the covalent attachment of a new group at        the site of the halogen atom;    -   (d) dienophile groups which are capable of participating in        Diels-Alder reactions such as, for example, maleimido groups;    -   (e) aldehyde or ketone groups such that subsequent        derivatization is possible via formation of carbonyl derivatives        such as, for example, imines, hydrazones, semicarbazones or        oximes, or via such mechanisms as Grignard addition or        alkyllithium addition;    -   (f) sulfonyl halide groups for subsequent reaction with amines,        for example, to form sulfonamides;    -   (g) thiol groups, which can be converted to disulfides, reacted        with aryl halides, or bonded to metals such as gold;    -   (h) amine or sulfhydryl groups, which can be, for example,        acylated, alkylated or oxidized;    -   (i) alkenes, which can undergo, for example, cycloadditions,        acylation, Michael addition. etc;    -   (j) epoxides, which can react with, for example, amines and        hydroxyl compounds;    -   (k) phosphoramidites and other standard functional groups useful        in nucleic acid synthesis;    -   (l) metal silicon oxide bonding; and    -   (m) metal bonding to reactive phosphorus groups (e.g.        phosphines) to form, for example, phosphate diester bonds.    -   (n) azides coupled to alkynes using copper catalyzed        cycloaddition click chemistry.

The reactive functional groups can be chosen such that they do notparticipate in, or interfere with, the chemical stability of theconjugate described herein. Alternatively, a reactive functional groupcan be protected from participating in the crosslinking reaction by thepresence of a protecting group.

In embodiments, X¹ is independently —Cl. In embodiments, X¹ isindependently —Br. In embodiments, X¹ is independently —I. Inembodiments, X¹ is independently —F. In embodiments, X² is independently—Cl. In embodiments, X² is independently —Br. In embodiments, X² isindependently —I. In embodiments, X² is independently —F. Inembodiments, X³ is independently —Cl. In embodiments, X³ isindependently —Br. In embodiments, X³ is independently —I. Inembodiments, X³ is independently —F. In embodiments, X⁴ is independently—Cl. In embodiments, X⁴ is independently —Br. In embodiments, X⁴ isindependently —I. In embodiments, X⁴ is independently —F. Inembodiments, X⁵ is independently —Cl. In embodiments, X⁵ isindependently —Br. In embodiments, X⁵ is independently —I. Inembodiments, X⁵ is independently —F. In embodiments, X⁶ is independently—Cl. In embodiments, X⁶ is independently —Br. In embodiments, X⁶ isindependently —I. In embodiments, X⁶ is independently —F. Inembodiments, X^(A) is independently —Cl. In embodiments, X^(A) isindependently —Br. In embodiments, X^(A) is independently —I. Inembodiments, X^(A) is independently —F.

In embodiments, the compound has the formula:

W¹, R¹, R², R³, R⁴, R⁵, L¹, L², L⁴, L⁵, z1, z2, and z3 are as describedherein.

In embodiments, the compound has the formula:

W¹, R¹, R², R³, R⁴, R⁵, L⁴, L⁵, z1, z2, and z3 are as described herein.Y is 0 or 1. In embodiments, Y is 0. In embodiments, Y is 1.

In embodiments, the compound has the formula:

wherein W¹, Y, R¹, R², R³, R⁴, R⁵, L⁴, L⁵, z1, z2, and z3 are asdescribed herein.

In embodiments, R¹ is independently halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH, —NH₂, —COOH, —CO NH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(1A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(1A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(1A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(1A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(1A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(1A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X¹ is independently—F, —Cl, —Br, or —I. In embodiments, R¹ is independently hydrogen. Inembodiments, R¹ is independently methyl. In embodiments, R¹ isindependently ethyl. In embodiments, R¹ is independently hydrogen, oxo,halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —OCX¹ ₃, —OCH₂X¹, —OCHX¹ ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R¹ substituents may optionally be joined toform an R^(1A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(1A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(1A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(1A)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, two adjacent R¹ substituents may optionallybe joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(1A) is independently oxo, halogen, —CX^(1A) ₃, —CHX^(1A) ₂,—CH₂X^(1A), —OCX^(1A) ₃, —OCH₂X^(1A), —OCHX^(1A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(1B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(1B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(1B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(1B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(1B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(1B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(1A) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(1A) isindependently oxo, halogen, —CX^(1A) ₃, —CHX^(1A) ₂, —CH₂X^(1A),—OCX^(1A) ₃, —OCH₂X^(1A), —OCHX^(1A) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(1B) is independently oxo, halogen, —CX^(1B) ₃, —CHX^(1B) ₂,—CH₂X^(1B), —OCX^(1B) ₃, —OCH₂X^(1B), —OCHX^(1B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(1C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(1C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(1C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(1C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(1C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(1C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(1B) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(1B) isindependently oxo, halogen, —CX^(1B) ₃, —CHX^(1B) ₂, —CH₂X^(1B),—OCX^(1B) ₃, —OCH₂X^(1B), —OCHX^(1B) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(1C) is independently oxo, halogen, —CX^(1C) ₃, —CHX^(1C) ₂,—CH₂X^(1C), —OCX^(1C) ₃, —OCH₂X^(1C), —OCHX^(1C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). X^(1C) is independently—F, —Cl, —Br, or —I.

In embodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —CH₂X²,—OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH, —NH₂, —COOH, —CO NH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(2A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(2A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(2A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(2A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(2A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(2A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X² is independently—F, —Cl, —Br, or —I. In embodiments, R² is independently hydrogen. Inembodiments, R² is independently methyl. In embodiments, R² isindependently ethyl. In embodiments, R² is independently hydrogen, oxo,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —OCX² ₃, —OCH₂X², —OCHX² ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered or 5 to 6 membered), unsubstituted aryl (e.g.,C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R² substituents may optionally be joined toform an R^(2A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(2A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(2A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(2A)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, two adjacent R² substituents may optionallybe joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(2A) is independently oxo, halogen, —CX^(2A) ₃, —CHX^(2A) ₂,—CH₂X^(2A), —OCX^(2A) ₃, —OCH₂X^(2A), —OCHX^(2A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(2B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(2B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(2B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(2B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(2B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(2B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(2A) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(2A) isindependently oxo, halogen, —CX^(2A) ₃, —CHX^(2A) ₂, —CH₂X^(2A),—OCX^(2A) ₃, —OCH₂X^(2A), —OCHX^(2A) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(2B) is independently oxo, halogen, —CX^(2B) ₃, —CHX^(2B) ₂,—CH₂X^(2B), —OCX^(2B) ₃, —OCH₂X^(2B), —OCHX^(2B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(2C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(2C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(2C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(2C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(2C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(2C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(2B) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(2B) isindependently oxo, halogen, —CX^(2B) ₃, —CHX^(2B) ₂, —CH₂X^(2B),—OCX^(2B) ₃, —OCH₂X^(2B), —OCHX^(2B) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(2C) is independently oxo, halogen, —CX^(2C) ₃, —CHX^(2C) ₂,—CH₂X^(2C), —OCX^(2C) ₃, —OCH₂X^(2C), —OCHX^(2C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). X^(2C) is independently—F, —Cl, —Br, or —I.

In embodiments, R³ is independently halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³,—OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —OH, —NH₂, —COOH, —CO NH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(3A)-substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(3A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(3A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(3A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(3A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(3A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X³ is independently—F, —Cl, —Br, or —I. In embodiments, R³ is independently hydrogen. Inembodiments, R³ is independently methyl. In embodiments, R³ isindependently ethyl. In embodiments, R³ is independently hydrogen, oxo,halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCH₂X³, —OCHX³ ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, two adjacent R³ substituents may optionally be joined toform an R^(3A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆). R^(3A)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(3A)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(3A)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, two adjacent R³ substituents may optionallybe joined to form an unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(3A) is independently oxo, halogen, —CX^(3A) ₃, —CHX^(3A) ₂,—CH₂X^(3A), —OCX^(3A) ₃, —OCH₂X^(3A), —OCHX^(3A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(3B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(3B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(3B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(3B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(3B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(3B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(3A) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(3A) isindependently oxo, halogen, —CX^(3A) ₃, —CHX^(3A) ₂, —CH₂X^(3A),—OCX^(3A) ₃, —OCH₂X^(3A), —OCHX^(3A) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(3B) is independently oxo, halogen, —CX^(3B) ₃, —CHX^(3B) ₂,—CH₂X^(3B), —OCX^(3B) ₃, —OCH₂X^(3B), —OCHX^(3B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(3C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂). R^(3C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(3C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(3C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(3C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(3C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(3B) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(3B) isindependently oxo, halogen, —CX^(3B) ₃, —CHX^(3B) ₂, —CH₂X^(3B),—OCX^(3B) ₃, —OCH₂X^(3B), —OCHX^(3B) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(3C) is independently oxo, halogen, —CX^(3C) ₃, —CHX^(3C) ₂,—CH₂X^(3C), —OCX^(3C) ₃, —OCH₂X^(3C), —OCHX^(3C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). X^(3C) is independently—F, —Cl, —Br, or —I.

In embodiments, R⁴ is independently hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂,—CH₂X⁴, —OCX⁴ ₃, —OCH₂X⁴, —OCHX⁴ ₂, —CN, —OH, —NH₂, —COOH, —CO NH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(4A)-substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(4A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(4A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(4A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(4A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(4A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X⁴ is independently—F, —Cl, —Br, or —I. In embodiments, R⁴ is independently hydrogen. Inembodiments, R⁴ is independently methyl. In embodiments, R⁴ isindependently ethyl. In embodiments, R⁴ is independently hydrogen, oxo,halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —OCX⁴ ₃, —OCH₂X⁴, —OCHX⁴ ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

R^(4A) is independently oxo, halogen, —CX^(4A) ₃, —CHX^(4A) ₂,—CH₂X^(4A), —OCX^(4A) ₃, —OCH₂X^(4A), —OCHX^(4A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(4B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(4B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(4B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(4B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(4B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(4B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(4A) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(4A) isindependently oxo, halogen, —CX^(4A) ₃, —CHX^(4A) ₂, —CH₂X^(4A),—OCX^(4A) ₃, —OCH₂X^(4A), —OCHX^(4A) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(4B) is independently oxo, halogen, —CX^(4B) ₃, —CHX^(4B) ₂,—CH₂X^(4B), —OCX^(4B) ₃, —OCH₂X^(4B), —OCHX^(4B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(4C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(4C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(4C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(4C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(4C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(4C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(4B) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(4B) isindependently oxo, halogen, —CX^(4B) ₃, —CHX^(4B) ₂, —CH₂X^(4B),—OCX^(4B) ₃, —OCH₂X^(4B), —OCHX^(4B) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(4C) is independently oxo, halogen, —CX^(4C) ₃, —CHX^(4C) ₂,—CH₂X^(4C), —OCX^(4C) ₃, —OCH₂X^(4C), —OCHX^(4C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). X^(4C) is independently—F, —Cl, —Br, or —I.

In embodiments, R⁵ is independently hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂,—CH₂X⁵, —OCX⁵ ₃, —OCH₂X⁵, —OCHX⁵ ₂, —CN, —OH, —NH₂, —COOH, —CO NH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(5A)-substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(5A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(5A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(5A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(5A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(5A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X⁵ is independently—F, —Cl, —Br, or —I. In embodiments, R⁵ is independently hydrogen. Inembodiments, R⁵ is independently methyl. In embodiments, R⁵ isindependently ethyl. In embodiments, R⁵ is independently hydrogen, oxo,halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —OCX⁵ ₃, —OCH₂X⁵, —OCHX⁵ ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂) unsubstitutedheteroalkyl. (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered,or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered,4 to 6 membered, 4 to 5 membered or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

R^(5A) is independently oxo, halogen, —CX^(5A) ₃, —CHX^(5A) ₂,—CH₂X^(5A), —OCX^(5A) ₃, —OCH₂X^(5A), —OCHX^(5A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(5B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(5B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(5B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(5B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(5B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(5B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(5A) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(5A) isindependently oxo, halogen, —CX^(5A) ₃, —CHX^(5A) ₂, —CH₂X^(5A),—OCX^(5A) ₃, —OCH₂X^(5A), —OCHX^(5A) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₄H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered 4to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(5B) is independently oxo, halogen, —CX^(5B) ₃, —CHX^(5B) ₂,—CH₂X^(5B), —OCX^(5B) ₃, —OCH₂X^(5B), —OCHX^(5B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(5C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(5C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(5C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(5C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(5C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(5C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(5B) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(5B) isindependently oxo, halogen, —CX^(5B) ₃, —CHX^(5B) ₂, —CH₂X^(5B),—OCX^(5B) ₃, —OCH₂X^(5B), —OCHX^(5B) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(5C) is independently oxo, halogen, —CX^(5C) ₃, —CHX^(5C) ₂,—CH₂X^(5C), —OCX^(5C) ₃, —OCH₂X^(5C), —OCHX^(5C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). X^(5C) is independently—F, —Cl, —Br, or —I.

In embodiments, R⁶ is independently hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —OH, —NH₂, —COOH, —CO NH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, R^(6A)-substitutedor unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R^(6A)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(6A)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(6A)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(6A)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(6A)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X⁶ is independently—F, —Cl, —Br, or —I. In embodiments, R⁶ is independently hydrogen. Inembodiments, R⁶ is independently methyl. In embodiments, R⁶ isindependently ethyl. In embodiments, R⁶ is independently hydrogen, oxo,halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —OCX⁶ ₃, —OCH₂X⁶, —OCHX⁶ ₂, —CN, —OH,—NH₂, —COOH, —CO NH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

R^(6A) is independently oxo, halogen, —CX^(6A) ₃, —CHX^(6A) ₂,—CH₂X^(6A), —OCX^(6A) ₃, —OCH₂X^(6A), —OCHX^(6A) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(6B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(6B)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(6B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(6B)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(6B)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(6B)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(6A) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(6A) isindependently oxo, halogen, —CX^(6A) ₃, —CHX^(6A) ₂, —CH₂X^(6A),—OCX^(6A) ₃, —OCH₂X^(6A), —OCHX^(6A) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(6B) is independently oxo, halogen, —CX^(6B) ₃, —CHX^(6B) ₂,—CH₂X^(6B), —OCX^(6B) ₃, —OCH₂X^(6B), —OCHX^(6B) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,R^(6C)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), R^(6C)-substituted or unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),R^(6C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆,C₄-C₆, or C₅-C₆), R^(6C)-substituted or unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(6C)-substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or R^(6C)-substituted or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered). X^(6B) isindependently —F, —Cl, —Br, or —I. In embodiments, R^(6B) isindependently oxo, halogen, —CX^(6B) ₃, —CHX^(6B) ₂, —CH₂X^(6B),—OCX^(6B) ₃, —OCH₂X^(6B), —OCHX^(6B) ₂, —CN, —OH, —NH₂, —COO H, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(6C) is independently oxo, halogen, —CX^(6C) ₃, —CHX^(6C) ₂,—CH₂X^(6C), —OCX^(6C) ₃, —OCH₂X^(6C), —OCHX^(6C) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). X^(6C) is independently—F, —Cl, —Br, or —I.

In embodiments, R⁷ is independently hydrogen, —CX⁷ ₃, —CN, —COOH,—CONH₂, —CHX⁷ ₂, —CH₂X⁷, R^(7A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(7A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(7A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(7A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(7A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(7A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X⁷ is independently —F, —Cl, —Br, or —I. In embodiments,R⁷ is independently hydrogen. In embodiments, R⁷ is independentlymethyl. In embodiments, R⁷ is independently ethyl. In embodiments, R⁷ isindependently hydrogen, CX⁷ ₃, —CN, —COOH, —CONH₂, —CHX⁷ ₂, —CH₂X⁷,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁷ and R⁸ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(7A)-substituted or unsubstitutedheterocycloalkyl or R^(7A)-substituted or unsubstituted heteroaryl. Inembodiments, R⁷ and R⁸ substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(7A)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(7A)-substituted or unsubstituted 5 to6 membered heteroaryl. In embodiments, R⁷ and R⁸ substituents bonded tothe same nitrogen atom may optionally be joined to form an unsubstituted3 to 6 membered heterocycloalkyl or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(7A)-substituted orunsubstituted piperazinyl. In embodiments, R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form aR^(7A)-substituted or unsubstituted piperidinyl. In embodiments, R⁷ andR⁸ substituents bonded to the same nitrogen atom may optionally bejoined to form a R^(7A)-substituted or unsubstituted pyrrolidinyl. Inembodiments, R⁷ and R⁸ substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(7A)-substituted or unsubstitutedazetidinyl. In embodiments, R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(7A)-substituted orunsubstituted morpholinyl. In embodiments, R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form aR^(7A)-substituted or unsubstituted azeridinyl.

R^(7A) is independently oxo, halogen, —CX^(7A) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(7A) ₂, —CH₂X^(7A), —OCX^(7A) ₃, —OCH₂X^(7A),—OCHX^(7A) ₂, R^(7B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(7B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3membered), R^(7B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(7B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(7B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(7B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(7A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(7A) is independently oxo, halogen, —CX^(7A) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(7A) ₂, —CH₂X^(7A), —OCX^(7A) ₃, —OCH₂X^(7A),—OCHX^(7A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂)unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(7B) is independently oxo, halogen, —CX^(7B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(7B) ₂, —CH₂X^(7B), —OCX^(7B) ₃, —OCH₂X^(7B),—OCHX^(7B) ₂, R^(7C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(7C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3membered), R^(7C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(7C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(7C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(7C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(7B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(7B) is independently oxo, halogen, —CX^(7B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(7B) ₂, —CH₂X^(7B), —OCX^(7B) ₃, —OCH₂X^(7B),—OCHX^(7B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(7C) is independently oxo, halogen, —CX^(7C) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(7C) ₂, —CH₂X^(7C), —OCX^(7C) ₃, —OCH₂X^(7C),—OCHX^(7C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^(7C) isindependently —F, —Cl, —Br, or —I.

In embodiments, R⁸ is independently hydrogen, —CX⁸ ₃, —CN, —COOH,—CONH₂, —CHX⁸ ₂, —CH₂X⁸, R^(8A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(8A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(8A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(8A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(8A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(8A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X⁸ is independently —F, —Cl, —Br, or —I. In embodiments,R⁸ is independently hydrogen. In embodiments, R⁸ is independentlymethyl. In embodiments, R⁸ is independently ethyl. In embodiments, R⁸ isindependently hydrogen, —CX⁸ ₃, —CN, —COOH, —CONH₂, —CHX⁸ ₂, —CH₂X⁸,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁸ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(8A)-substituted or unsubstitutedheterocycloalkyl or R^(8A)-substituted or unsubstituted heteroaryl. Inembodiments, R⁸ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(8A)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(8A)-substituted or unsubstituted 5 to6 membered heteroaryl. In embodiments, R⁸ and R⁷ substituents bonded tothe same nitrogen atom may optionally be joined to form an unsubstituted3 to 6 membered heterocycloalkyl or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R⁸ and R⁷ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(8A)-substituted orunsubstituted piperazinyl. In embodiments, R⁸ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form aR^(8A)-substituted or unsubstituted piperidinyl. In embodiments, R⁸ andR⁷ substituents bonded to the same nitrogen atom may optionally bejoined to form a R^(8A)-substituted or unsubstituted pyrrolidinyl. Inembodiments, R⁸ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form a R^(8A)-substituted or unsubstitutedazetidinyl. In embodiments, R⁸ and R⁷ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(8A)-substituted orunsubstituted morpholinyl. In embodiments, R⁸ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form aR^(8A)-substituted or unsubstituted azeridinyl.

R^(8A) is independently oxo, halogen, —CX^(8A) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(8A) ₂, —CH₂X^(8A), —OCX^(8A) ₃, —OCH₂X^(8A),——OCHX^(8A) ₂, R^(8B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(8B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3membered), R^(8B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(8B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(8B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(8B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(8A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(8A) is independently oxo, halogen, —CX^(8A) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(8A) ₂, —CH₂X^(8A), —OCX^(8A) ₃, —OCH₂X^(8A),—OCHX^(8A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(8B) is independently oxo, halogen, —CX^(8B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(8B) ₂, —CH₂X^(8B), —OCX^(8B) ₃, —OCH₂X^(8B),—OCHX^(8B) ₂, R^(8C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(8C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered or 2 to 3membered), R^(8C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(8C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(8C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(8C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(8B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(8B) is independently oxo, halogen, —CX^(8B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(8B) ₂, —CH₂X^(8B), —OCX^(8B) ₃, —OCH₂X^(8B),—OCHX^(8B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(8C) is independently oxo, halogen, —CX^(8C) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(8C) ₂, —CH₂X^(8C), —OCX^(8C) ₃, —OCH₂X^(8C),—OCHX^(8C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^(8C) isindependently —F, —Cl, —Br, or —I.

In embodiments, R⁹ is independently hydrogen, —CX⁹ ₃, —CN, —COOH,—CONH₂, —CHX⁹ ₂, —CH₂X⁹, R^(9A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(9A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(9A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(9A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(9A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(9A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X⁹ is independently —F, —Cl, —Br, or —I. In embodiments,R⁹ is independently hydrogen. In embodiments, R⁹ is independentlymethyl. In embodiments, R⁹ is independently ethyl. In embodiments, R⁹ isindependently hydrogen, —CX⁹ ₃, —CN, —COOH, —CONH₂, —CHX⁹ ₂, —CH₂X⁹,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

R^(9A) is independently oxo, halogen, —CX^(9A) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(9A) ₂, —CH₂X^(9A), —OCX^(9A) ₃, —OCH₂X^(9A),—OCHX^(9A) ₂, R^(9B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(9B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3membered), R^(9B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(9B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(9B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(9B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(9A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(9A) is independently oxo, halogen, —CX^(9A) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(9A) ₂, —CH₂X^(9A), —OCX^(9A) ₃, —OCH₂X_(9A),—OCHX^(9A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(9B) is independently oxo, halogen, —CX^(9B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(9B) ₂, —CH₂X^(9B), —OCX^(9B) ₃, —OCH₂X^(9B),—OCHX^(9B) ₂, R^(9C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(9C)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3membered), R^(9C)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(9C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(9C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(9C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(9B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(9B) is independently oxo, halogen, —CX^(9B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(9B) ₂, —CH₂X^(9B), —OCX^(9B) ₃, —OCH₂X^(9B),—OCHX^(9B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(9C) is independently oxo, halogen, —CX^(9C) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(9C) ₂, —CH₂X^(9C), —OCX^(9C) ₃, —OCH₂X^(9C),—OCHX^(9C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X^(9C) isindependently —F, —Cl, —Br, or —I.

In embodiments, R¹⁰ is independently hydrogen, —CX¹⁰ ₃, —CN, —COOH,—CONH₂, —CHX¹⁰ ₂, —CH₂X¹⁰, R^(10A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(10A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(10A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(10A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(10A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(10A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹⁰ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹⁰ is independently hydrogen. In embodiments, R¹⁰ isindependently methyl. In embodiments, R¹⁰ is independently ethyl. Inembodiments, R¹⁰ is independently hydrogen, —CX¹⁰ ₃, —CN, —COOH, —CONH₂,—CHX¹⁰ ₂, —CH₂X¹⁰, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(10A) is independently oxo, halogen, —CX^(10A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(10A) ₂, —CH₂X^(10A), —OCX^(10A) ₃, —OCH₂X^(10A),—OCHX^(10A) ₂, R^(10B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(10B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered or2 to 3 membered), R^(10B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(10B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(10B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(10B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(10A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(10A) is independently oxo, halogen, —CX^(10A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(10A) ₂, —CH₂X^(10A), —OCX^(10A) ₃, —OCH₂X^(10A),—OCHX^(10A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(10B) is independently oxo, halogen, —CX^(10B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(10B) ₂, —CH₂X^(10B), —OCX^(10B) ₃, —OCH₂X^(10B),—OCHX^(10B) ₂, R^(10C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(10C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(10C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(10C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(10C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(10C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(10B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(10B) is independently oxo, halogen, —CX^(10B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(10B) ₂, —OCX₂X^(10B), —OCX^(10B) ₃,—OCH₂C^(10B), —OCHX^(10B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(10C) is independently oxo, halogen, —CX^(10C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)OH,—NHC(O)OH, —NHOH, —OCX^(10C) ₂, —CH₂X^(10C), —OCX^(10C) ₃, —OCH₂X^(10C),—OCHX^(10C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(10C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹¹ is independently hydrogen, —CX¹¹ ₃, —CN, —COOH,—CONH₂, —CHX¹¹ ₂, —CH₂X¹¹, R^(11A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(11A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(11A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(11A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(11A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(11A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹¹ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹¹ is independently hydrogen. In embodiments, R¹¹ isindependently methyl. In embodiments, R¹¹ is independently ethyl. Inembodiments, R¹¹ is independently hydrogen, —CX¹¹ ₃, —CN, —COOH, —CONH₂,—CHX¹¹ ₂, —CH₂X¹¹, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R¹¹ and R¹² substituents bonded to the same nitrogenatom may optionally be joined to form a R^(11A)-substituted orunsubstituted heterocycloalkyl or R^(11A)-substituted or unsubstitutedheteroaryl. In embodiments, R¹¹ and R¹² substituents bonded to the samenitrogen atom may optionally be joined to form a R^(11A)-substituted orunsubstituted 3 to 6 membered heterocycloalkyl or R^(11A)-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹¹ and R¹²substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹¹ and R¹²substituents bonded to the same nitrogen atom may optionally be joinedto form a R^(11A)-substituted or unsubstituted piperazinyl. Inembodiments, R¹¹ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form a R^(11A)-substituted or unsubstitutedpiperidinyl. In embodiments, R¹¹ and R¹² substituents bonded to the samenitrogen atom may optionally be joined to form a R^(11A)-substituted orunsubstituted pyrrolidinyl. In embodiments, R¹¹ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(11A)-substituted or unsubstituted azetidinyl. In embodiments, R¹¹ andR¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a R^(11A)-substituted or unsubstituted morpholinyl. Inembodiments, R¹¹ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form a R^(11A)-substituted or unsubstitutedazeridinyl.

R^(11A) is independently oxo, halogen, —CX^(11A) ₃, —CN, —OH, —NH₂,—COON, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(11A) ₂, —CH₂X^(11A), —OCX^(11A) ₃, —OCH₂X^(11A),—OCHX^(11A) ₂, R^(11B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(11B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(11B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(11B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered or 5 to 6 membered), R^(11B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(11B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(11A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(11A) is independently oxo, halogen, —CX^(11A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(11A) ₂, —CH₂X^(11A), —OCX^(11A) ₃, —OCH₂X^(11A),—OCHX^(11A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(11B) is independently oxo, halogen, —CX^(11B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(11B) ₂, —CH₂X^(11B), —OCX^(11B) ₃, —OCH₂X^(11B),—OCHX^(11B) ₂, R^(11C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₄, C₁-C₄, or C₁-C₂), R^(11C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(11C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(11C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(11C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(11C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(11B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(11B) is independently oxo, halogen, —CX^(11B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(11B) ₂, —CH₂X^(11B), —OCX^(11B) ₃, —OCH₂X^(11B),—OCHX^(11B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl.(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(11C) is independently oxo, halogen, —CX^(11C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(11C) ₂, —CH₂X^(11C), —OCX^(11C) ₃, —OCH₂X^(11C),—OCHX^(11C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(11C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹² is independently hydrogen, —CX¹² ₃, —CN, —COOH,—CONH₂, —CHX¹² ₂, —CH₂X¹², R^(12A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(12A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered 4 to 6membered, or 2 to 3 membered), R^(12A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(12A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(12A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(12A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹² is independently —F, —Cl, —Br, or —I. Inembodiments, R¹² is independently hydrogen. In embodiments, R¹² isindependently methyl. In embodiments, R¹² is independently ethyl. Inembodiments, R¹² is independently hydrogen, —CX¹² ₃, —CN, —COOH, —CONH₂,—CHX¹² ₂, —CH₂X¹², unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R¹² and R¹¹ substituents bonded to the same nitrogenatom may optionally be joined to form a R^(12A)-substituted orunsubstituted heterocycloalkyl or R^(12A)-substituted or unsubstitutedheteroaryl. In embodiments, R¹² and R¹¹ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(12A)-substituted orunsubstituted 3 to 6 membered heterocycloalkyl or R^(12A)-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹² and R¹¹substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹² and R¹¹substituents bonded to the same nitrogen atom may optionally be joinedto form a R^(12A)-substituted or unsubstituted piperazinyl. Inembodiments, R¹² and R¹¹ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(12A)-substituted or unsubstitutedpiperidinyl. In embodiments, R¹² and R¹¹ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(12A)-substituted orunsubstituted pyrrolidinyl. In embodiments, R¹² and R¹¹ substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(12A)-substituted or unsubstituted azetidinyl. In embodiments, R¹² andR¹¹ substituents bonded to the same nitrogen atom may optionally bejoined to form a R^(12A)-substituted or unsubstituted morpholinyl. Inembodiments, R¹² and R¹¹ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(12A)-substituted or unsubstitutedazeridinyl.

R^(12A) is independently oxo, halogen, —CX^(12A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(12A) ₂, —CH₂X^(12A), —OCX^(12A) ₃, —OCH₂X^(12A),—OCHX^(12A) ₂, R^(12B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(12B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(12B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(12B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(12B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(12B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(12A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(12A) is independently oxo, halogen, —CX^(12A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(12A) ₂, —CH₂X^(12A), —OCX^(12A) ₃, —OCH₂X^(12A),—OCHX^(12A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).

R^(12B) is independently oxo, halogen, —CX^(12B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(12B) ₂, —CH₂X^(12B), —OCX^(12B) ₃, —OCH₂X^(12B),—OCHX^(12B) ₂, R^(12C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(12C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(12C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(12C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(12C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(12C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(12B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(12B) is independently oxo, halogen, —CX^(12B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(12B) ₂, —CH₂X^(12B), —OCX^(12B) ₃, —OCH₂X^(12B),—OCHX^(12B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(12C) is independently oxo, halogen, —CX^(12C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(12C) ₂, —CH₂X^(12C), —OCX^(12C) ₃, —OCH₂X^(12C),—OCHX^(12C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(12C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹³ is independently hydrogen, —CX¹³ ₃, —CN, —COOH,—CONH₂, —CHX¹³ ₂, —CH₂X¹³, R^(13A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(13A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(13A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(13A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(13A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(13A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹³ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹³ is independently hydrogen. In embodiments, R¹³ isindependently methyl. In embodiments, R¹³ is independently ethyl. Inembodiments, R¹³ is independently hydrogen, —CX¹³ ₃, —CN, —COOH, —CONH₂,—CHX¹³ ₂, —CH₂X¹³, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).

R^(13A) is independently oxo, halogen, —CX^(13A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(13A) ₂, —CH₂X^(13A), —OCX^(13A) ₃, —OCH₂X^(13A),—OCHX^(13A) ₂, R^(13B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(13B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(13B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(13B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(13B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(13B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(13A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(13A) is independently oxo, halogen, —CX^(13A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(13A) ₂, —CH₂X^(13A), —OCX^(13A) ₃, —OCH₂X^(13A),—OCHX^(13A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).

R^(13B) is independently oxo, halogen, —CH^(13B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(13B) ₂, —CH₂X^(13B), —OCX^(13B) ₃, —OCH₂X^(13B),—OCHX^(13B) ₂, R^(13C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(13C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(13C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(13C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(13C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(13C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(13B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(13B) is independently oxo, halogen, —CX^(13B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(13B) ₂, —CH₂X^(13B), —OCX^(13B) ₃, —OCH₂X^(13B),—OCHX^(13B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(13C) is independently oxo, halogen, —CX^(13C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(13C) ₂, —CH₂X^(13C), —OCX^(13C) ₃, —OCH₂X^(13C),—OCHX^(13C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(13C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹⁴ is independently hydrogen, —CX¹⁴ ₃, —CN, —COOH,—CONH₂, —CHX¹⁴ ₂, —CH₂X¹⁴, R^(14A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(14A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(14A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). R^(14A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered). R^(14A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(14A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹⁴ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹⁴ is independently hydrogen. In embodiments, R¹⁴ isindependently methyl. In embodiments, R¹⁴ is independently ethyl. Inembodiments, R¹⁴ is independently hydrogen, —CX¹⁴ ₃, —CN, —COOH, —CONH₂,—CHX¹⁴ ₂, —CH₂X¹⁴, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(14A) is independently oxo, halogen, —CX^(14A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(14A) ₂, —CH₂X^(14A), —OCX^(14A) ₃, —OCH₂X^(14A),—OCHX^(14A) ₂, R^(14B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(14B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(14B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(14B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(14B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(14B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(14A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(14A) is independently oxo, halogen, —CX^(14A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(14A) ₂, —CH₂X^(14A), —OCX^(14A) ₃, —OCH₂X^(14A),—OCHX^(14A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).

R^(14B) is independently oxo, halogen, —CX^(14B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(14B) ₂, —CH₂X^(14B, —OCX) ^(14B) ₃,—OCH₂X^(14B), —OCHX^(14B) ₂, R^(14C)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(14C)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(14C)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(14C)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(14C)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(14C)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X^(14B) is independently —F, —Cl, —Br, or —I. Inembodiments, R^(14B) is independently oxo, halogen, —CX^(14B) ₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHC(O)H, —NHC(O)OH, —NHOH, —CHX^(14B) ₂, —CH₂X^(14B), —OCX^(14B) ₃,—OCH₂X^(14B), —OCHX^(14B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(14C) is independently oxo, halogen, —CX^(14C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(14C) ₂, —CH₂X^(14C), —OCX^(14C) ₃, —OCH₂X^(14C),—OCHX^(14C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(14C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹⁵ is independently hydrogen, —CX¹⁵ ₃, —CN, —COOH,—CONH₂, —CHX¹⁵ ₂, —CH₂X¹⁵, R^(15A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(15A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(15A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆). R^(15A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered 4to 5 membered, or 5 to 6 membered). R^(15A)-substituted or unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or R^(15A)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X¹⁵ is independently —F, —Cl, —Br, or —I. In embodiments, R¹⁵is independently hydrogen. In embodiments, R¹⁵ is independently methyl.In embodiments, R¹⁵ is independently ethyl. In embodiments, R¹⁵ isindependently hydrogen, —CX¹⁵ ₃, —CN, —COOH, —CONH₂, —CHX¹⁵ ₂, —CH₂X¹⁵,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹⁵ and R¹⁶ substituents bonded to the same nitrogenatom may optionally be joined to form a R^(15A)-substituted orunsubstituted heterocycloalkyl or R^(15A)-substituted or unsubstitutedheteroaryl. In embodiments, R¹⁵ and R¹⁶ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(15A)-substituted orunsubstituted 3 to 6 membered heterocycloalkyl or R^(15A)-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁵ and R¹⁶substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁵ and R¹⁶substituents bonded to the same nitrogen atom may optionally be joinedto form a R^(15A)-substituted or unsubstituted piperazinyl. Inembodiments, R¹⁵ and R¹⁶ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(15A)-substituted or unsubstitutedpiperidinyl. In embodiments, R¹⁵ and R¹⁶ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(15A)-substituted orunsubstituted pyrrolidinyl. In embodiments, R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(15A)-substituted or unsubstituted azetidinyl. In embodiments, R¹⁵ andR¹⁶ substituents bonded to the same nitrogen atom may optionally bejoined to form a R^(15A)-substituted or unsubstituted morpholinyl. Inembodiments, R¹⁵ and R¹⁶ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(15A)-substituted or unsubstitutedazeridinyl.

R^(15A) is independently oxo, halogen, —CX^(15A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(15A) ₂, —CH₂X^(15A), —OCX^(15A) ₃, —OCH₂X^(15A),—OCHX^(15A) ₂, R^(15B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(15B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(15B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(15B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(15B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(15B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(15A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(15A) is independently oxo, halogen, —CX^(15A) ₃, —CN, —OH, —COOH,—CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(15A) ₂, —CH₂X^(15A), —OCX^(15A) ₃, —OCH₂X^(15A),—OCHX^(15A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(15B) is independently oxo, halogen, —CX^(15B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(15B) ₂, —CH₂X^(15B), —OCX^(15B) ₃, —OCH₂X^(15B),—OCHX^(15B) ₂, R^(15C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(15C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(15C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(15C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(15C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(15C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).X^(15B) is independently —F, —Cl, —Br, or —I. In embodiments, R^(15B) isindependently oxo, halogen, —CX^(15B) ₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H, —NHC(O)OH,—NHOH, —CHX^(15B) ₂, —CH₂X^(15B), —OCX^(15B) ₃, —OCH₂X^(15B),—OCHX^(15B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(15C) is independently oxo, halogen, —CX^(15C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(15C) ₂, —CH₂X^(15C), —OCX^(15C) ₃, —OCH₂X^(15C),—OCHX^(15C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(15C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹⁶ is independently hydrogen, —CX¹⁶ ₃, —CN, —COOH,—CONH₂, —CHX¹⁶ ₂, —CH₂X¹⁶, R^(16A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(16A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(16A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(16A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(16A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(16A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹⁶ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹⁶ is independently hydrogen. In embodiments, R¹⁶ isindependently methyl. In embodiments, R¹⁶ is independently ethyl. Inembodiments, R¹⁶ is independently hydrogen, —CX¹⁶ ₃, —CN, —COOH, —CONH₂,—CHX¹⁶ ₂, —CH₂X¹⁶, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

In embodiments, R¹⁶ and R¹⁵ substituents bonded to the same nitrogenatom may optionally be joined to form a R^(16A)-substituted orunsubstituted heterocycloalkyl or R^(16A)-substituted or unsubstitutedheteroaryl. In embodiments, R¹⁶ and R¹⁵ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(16A)-substituted orunsubstituted 3 to 6 membered heterocycloalkyl or R^(16A)-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁶ and R¹⁵substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁶ and R¹⁵substituents bonded to the same nitrogen atom may optionally be joinedto form a R^(16A)-substituted or unsubstituted piperazinyl. Inembodiments, R¹⁶ and R¹⁵ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(16A)-substituted or unsubstitutedpiperidinyl. In embodiments, R¹⁶ and R¹⁵ substituents bonded to the samenitrogen atom may optionally be joined to form a R^(16A)-substituted orunsubstituted pyrrolidinyl. In embodiments, R¹⁶ and R¹⁵ substituentsbonded to the same nitrogen atom may optionally be joined to form aR^(16A)-substituted or unsubstituted azetidinyl. In embodiments, R¹⁶ andR¹⁵ substituents bonded to the same nitrogen atom may optionally bejoined to form a R^(16A)-substituted or unsubstituted morpholinyl. Inembodiments, R¹⁶ and R¹⁵ substituents bonded to the same nitrogen atommay optionally be joined to form a R^(16A)-substituted or unsubstitutedazeridinyl.

R^(16A) is independently oxo, halogen, —CX^(16A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(16A) ₂, —CH₂X^(16A), —OCX^(16A) ₃, —OCH₂X^(16A),—OCHX^(16A) ₂, R^(16B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(16B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(16B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(16B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(16B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(16B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(16A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(16A) is independently oxo, halogen, —CX^(16A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(16A) ₂, —CH₂X^(16A), —OCX^(16A) ₃, —OCH₂X^(16A),—OCHX^(16A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).

R^(16B) is independently oxo, halogen, —CX^(16B) ₃, —CN, —OH, —NH₂,—COOH, —CONH, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(16B) ₂, —CH₂X^(16B), —OCX^(16B) ₃, —OCH₂X^(16B),—OCHX^(16B) ₂, R^(16C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(16C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(16C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(16C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(16C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(16C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).X^(16B) is independently —F, —Cl, —Br, or —I. In embodiments, R^(16B) isindependently oxo, halogen, —CX^(16B) ₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H, —NHC(O)OH,—NHOH, —CHX^(16B) ₂, —CH₂X^(16B), —OCX^(16B) ₃, —OCH₂X^(16B),—OCHX^(16B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (ea., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R^(16C) is independently oxo, halogen, —CX^(16C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(16C) ₂, —CH₂X^(16C), —OCX^(16C) ₃, —OCH₂X^(16C),—OCHX^(16C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(16C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹⁷ is independently hydrogen, —CX¹⁷ ₃, —CN, —COOH,—CONH₂, —CHX¹⁷ ₂, —CH₂X¹⁷, R^(17A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(17A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(17A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(17A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered), R^(17A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(17A)-substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). X¹⁷ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹⁷ is independently hydrogen. In embodiments, R¹⁷ isindependently methyl. In embodiments, R¹⁷ is independently ethyl. Inembodiments, R¹⁷ is independently hydrogen, —CX¹⁷ ₃, —CN, —COOH, —CONH₂,—CHX¹⁷ ₂, —CH₂X¹⁷, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(17A) is independently oxo, halogen, —CX^(17A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(17A) ₂, —CH₂X^(17A), —OCX^(17A) ₃, —OCH₂X^(17A),—OCHX^(17A) ₂, R^(17B)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(17B)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(17B)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(17B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(17B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(17B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(17A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(17A) is independently oxo, halogen, —CX^(17A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(17A) ₂, —CH₂X^(17A), —OCX^(17A) ₃, —OCH₂X^(17A),—OCHX^(17A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered.), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(17B) is independently oxo, halogen, —CX^(17B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(17B) ₂, —CH₂X^(17B), —OCX^(17B) ₃, —OCH₂X^(17B),—OCHX^(17B) ₂, R^(17C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(17C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(17C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(17C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(17C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(17C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(17B) is independently —F, —Cl, —Br, or —I. In embodiments,R^(17B) is independently oxo, halogen, —CX^(17B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(17B) ₂, —CH₂X^(17B), —OCX^(17B) ₃, —OCH₂X^(17B),—OCHX^(17B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R_(17C) is independently oxo, halogen, —CX^(17C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₇, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(17C) ₂, —CH₂X^(17C), —OCX^(17C) ₃, —OCH₂X^(17C),—OCHX^(17C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(17C) is independently —F, —Cl, —Br, or —I.

In embodiments, R¹⁸ is independently hydrogen, —CX¹⁸ ₃, —CN, —COOH,—CONH₂, —CHX¹⁸ ₂, —CH₂X¹⁸, R^(18A)-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R^(18A)-substituted orunsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), R^(18A)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(18A)-substituted orunsubstituted heterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered,4 to 5 membered, or 5 to 6 membered). R^(18A)-substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or R^(18A)-substituted orunsubstituted heteroaryl (e,g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered), X¹⁸ is independently —F, —Cl, —Br, or —I. Inembodiments, R¹⁸ is independently hydrogen. In embodiments, R¹⁸ isindependently methyl. In embodiments, R¹⁸ is independently ethyl. Inembodiments, R¹⁸ is independently hydrogen, —CX¹⁸ ₃, —CN, —COOH, —CONH₂,—CHX¹⁸ ₂, —CH₂X¹⁸, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(18A) is independently oxo, halogen, —CX^(18A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(18A) ₂, —OCX^(18A) ₃, —OCH₂X^(18A), —OCHX^(18A)₂, R^(18B)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R^(18B)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3membered), R^(18B)-substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), R^(18B)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(18B)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(18B)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(18A) is independently —F, —Cl, —Br, or —I. In embodiments,R^(18A) is independently oxo, halogen, —CX^(18A) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(18A) ₂, —CH₂X^(18A), —OCX^(18A) ₃, —OCH₂X^(18A),—OCHX^(18A) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered.), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R^(18B) is independently oxo, halogen, —CX^(18B) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(18B) ₂, —CH₂X^(18B), —OCX^(18B) ₃, —OCH₂X^(18B),—OCHX^(18B) ₂, R^(18C)-substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), R^(18C)-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R^(18C)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(18C)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R^(18C)-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R^(18C)-substituted or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered or 5 to 6 membered).X^(18B) is independently —F, —Cl, —Br, or —I. In embodiments, R^(18B) isindependently oxo, halogen, —CX^(18B) ₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H, —NHC(O)OH,—NHOH, —CHX^(18B) ₂, —CH₂X^(18B), —OCX^(18B) ₃, —OCH₂X^(18B),—OCHX^(18B) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered).

R^(18C) is independently oxo, halogen, —CX^(18C) ₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —SH, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHC(O)H,—NHC(O)OH, —NHOH, —CHX^(18C) ₂, —CH₂X^(18C), —OCX^(18C) ₃, —OCH₂X^(18C),—OCHX^(18C) ₂, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, or 2 to 3 membered), unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl(e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered), X^(18C) is independently —F, —Cl, —Br, or —I.

In embodiments, L¹ is independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R²³-substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂) orR²³-substituted or unsubstituted heteroalkylene(e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered). In embodiments, L¹is independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂) or unsubstituted heteroalkylene e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered).

R²³ is independently oxo, halogen, —CX²³ ₃, —CHX²³ ₂, —CH₂X²³, —OCX²³ ₃,—OCH₂X²³, —OCHX²³ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R²⁴-substituted or unsubstituted alkyl (e,a., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R²⁴-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R²⁴-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁴-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R²⁴-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R²⁴-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X²³ isindependently —F, —Cl, —Br, or —I. In embodiments, R²³ is independentlyoxo, halogen, —CX²³ ₃, —CHX²³ ₂, —CH₂X²³, —OCX²³ ₃, —OCH₂X²³, —OCHX²³ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R¹⁴ is independently oxo, halogen, —CX²⁴ ₃, —CHX²⁴ ₂, —CH₂X²⁴, —OCX²⁴ ₃,—OCH₂X²⁴, —OCHX²⁴ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)OH, —NHC(O)—OH, —NHOH, R²⁵-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R²⁵-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R²⁵-substituted or unsubstituted cycloalkyl (e.g.,C₂-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R²⁵-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R²⁵-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X²⁴ isindependently —F, —Cl, —Br, or —I. In embodiments, R²⁴ is independentlyoxo, halogen, —CX²⁴ ₃, —CHX²⁴ ₂, —CH₂X²⁴, —OCX²⁴ ₃, —OCH₂X²⁴, —OCHX²⁴ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R²⁵ is independently oxo, halogen, —CX²⁵ ₃, —CHX²⁵ ₂, —CH₂X²⁵, —OCX²⁵ ₃,—OCH₂X²⁵, —OCH²⁵ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X²⁵ is independently —F, —Cl, —Br, or —I.

In embodiments, L² is independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R²⁶-substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂) orR²⁶-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered). In embodiments,L² is independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—,—C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂) or unsubstituted heteroalkylene (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, or 2 to 3 membered).

R²⁶ is independently oxo, halogen, —CX²⁶ ₃, —CHX²⁶ ₂, —CH₂X²⁶, —OCX²⁶ ₃,—OCH₂X²⁶, —OCHX²⁶ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R²⁷-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R²⁷-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered.), R²⁷-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁷-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R²⁷-substituted or unsubstituted arylC₆-C₁₀ or phenyl), or R²⁷-substituted or unsubstituted heteroaryl (e.g.,5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X²⁶ isindependently —F, —Cl, —Br, or —I. In embodiments, R²⁶ is independentlyoxo, halogen, —CX²⁶ ₃, —CHX²⁶ ₂, —CH₂X²⁶, —OCX²⁶ ₃, —OCH₂X²⁶, —OCHX²⁶ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R²⁷ is independently oxo, halogen, —CX²⁷ ₃, —CHX²⁷ ₂, —CH₂X²⁷, —OCX²⁷ ₃,—OCH₂X²⁷, —OCHX²⁷ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R²⁸-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R²⁸-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R²⁸-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R²⁸-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R²⁸-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R²⁸-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X²⁷ isindependently —F, —Cl, —Br, or —I. In embodiments, R²⁷ is independentlyoxo, halogen, —CX²⁷ ₃, —CHX²⁷ ₂, —CH₂X²⁷, —OCX²⁷ ₃, —OCH₂X²⁷, —OCHX²⁷ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R²⁸ is independently oxo, halogen, —CX²⁸ ₃, —CHX²⁸ ₂, —CH₂X²⁸, —OCX²⁸ ₃,—OCH₂X²⁸, —OCHX²⁸ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X²⁸ is independently —F, —Cl, —Br, or —I.

In embodiments, L⁴¹ is independently a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R²⁹-substitutedor unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R²⁹-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), R²⁹-substitutedor unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R²⁹-substituted or unsubstituted heterocycloalkylene(e.g., 3 to 6membered, 4 to 6 membered 4 to 5 membered, or 5 to 6 membered),R²⁹-substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenyl), orR²⁹-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered). In embodiments, L^(4A) isindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkylene (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted arylene (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R²⁹ is independently oxo, halogen, —CX²⁹ ₃, —CHX²⁹ ₂, —CH₂X²⁹, —OCX²⁹ ₃,—OCH₂X²⁹, —OCHX²⁹ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁰-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³⁰-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³⁰-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³⁰-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³⁰-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X²⁹ isindependently —F, —Cl, —Br, or —I. In embodiments, R²⁹ is independentlyoxo, halogen, —CX²⁹ ₃, —CHX²⁹ ₂, —CH₂X²⁹, —OCX²⁹ ₃, —OCH₂X²⁹, —OCHX²⁹ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C_(C) ₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³⁰ is independently oxo, halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —CH₂X³⁰, —OCX³⁰ ₃,—OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³¹-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³¹-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³¹-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³¹-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³¹-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³¹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³⁰ isindependently —F, —Cl, —Br, or —I. In embodiments, R³⁰ is independentlyoxo, halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —CH₂X³⁰, —OCX³⁰ ₃, —OCH₂X³⁰, —OCHX³⁰ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³¹ is independently oxo, halogen, —CX³¹ ₃, —CHX³¹ ₂, —CH₂X³¹, —OCX³¹ ₃,—OCH₂X³¹, —OCHX³¹ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X³¹ is independently —F, —Cl, —Br, or —I.

In embodiments, L^(4B) is independently a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R³²-substitutedor unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R³²-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), e-substituted orunsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R³²-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R³²-substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenyl), orR³²-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered). In embodiments, L^(4B) isindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkylene (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted arylene (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R³² is independently oxo, halogen, —CX³² ₃, —CHX³² ₂, —CH₂X³², —OCX³² ₃,—OCH₂X³², —OCHX³² ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³³-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³³-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³³-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³³-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³³-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³² isindependently —F, —Cl, —Br, or —I. In embodiments, R³² is independentlyoxo, halogen, —CX³² ₃, —CHX³² ₂, —CH₂X³², —OCX³² ₃, —OCH₂X³², —OCHX³² ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³³ is independently oxo, halogen, —CX³³ ₃, —CHX³³ ₂, —CH₂X³³, —OCX³³ ₃,—OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁴-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³⁴-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³⁴-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁴-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³⁴-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³⁴-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³³ isindependently —F, —Cl, —Br, or —I. In embodiments, R³³ is independentlyoxo, halogen, —CX³³ ₃, —CHX³³ ₂, —CH₂X³³, —OCX³³ ₃, —OCH₂X³³, —OCHX³³ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³⁴ is independently oxo, halogen, —CX³⁴ ₃, —CHX³⁴ ₂, —CH₂X³⁴, —OCX³⁴ ₃,—OCH₂X³⁴, —OCHX³⁴ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X³⁴ is independently —F, —Cl, —Br, or —I.

In embodiments, L^(4C) is independently a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R³⁵-substitutedor unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R³⁵-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), R³⁵-substitutedor unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R³⁵-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R³⁵-substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenyl), orR³⁵-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered). In embodiments, L^(4C) isindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkylene (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted arylene (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R³⁵ is independently oxo, halogen, —CX³⁵ ₃, —CHX³⁵ ₂, —CH₂X³⁵, —OCX³⁵ ₃,—OCH₂X³⁵, —OCHX³⁵ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁶-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³⁶-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³⁶-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³⁶-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³⁵ isindependently —F, —Cl, —Br, or —I. In embodiments, R³⁵ is independentlyoxo, halogen, —CX³⁵ ₃, —CHX³⁵ ₂, —CH₂X³⁵, —OCX³⁵ ₃, —OCH₂X³⁵, —OCHX³⁵ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³⁶ is independently oxo, halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —CH₂X³⁶, —OCX³⁶ ₃,—OCH₂X³⁶, —OCHX³⁶ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁷-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³⁷-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³⁷-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁷-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³⁷-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³⁷-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³⁶ isindependently —F, —Cl, —Br, or —I. In embodiments, R³⁶ is independentlyoxo, halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —CH₂X³⁶, —OCX³⁶ ₃, —OCH₂X³⁶, —OCHX³⁶ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³⁷ is independently oxo, halogen, —CX³⁷ ₃, —CHX³⁷ ₂, —CH₂X³⁷, —OCX³⁷ ₃,—OCH₂X³⁷, —OCHX³⁷ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalicyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X³⁷ is independently —F, —Cl, —Br, or —I.

In embodiments, L^(5A) is independently a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R³⁸-substitutedor unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R³⁸-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), R³⁸-substitutedor unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R³⁸-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R³⁸-substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenyl), orR³⁸-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered). In embodiments, L^(5A) isindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkylene (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted arylene (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R³⁸ is independently oxo, halogen, —CX³⁸ ₃, —CHX³⁸ ₂, —CH₂X³⁸, —OCX³⁸ ₃,—OCH₂X³⁸, —OCHX³⁸ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R³⁹-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R³⁹-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R³⁹-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R³⁹-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R³⁹-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R³⁹-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³⁸ isindependently —F, —Cl, —Br, or —I. In embodiments, R³⁸ is independentlyoxo, halogen, —CX³⁸ ₃, —CHX³⁸ ₂, —CH₂X³⁸, —OCX³⁸ ₃, —OCH₂X³⁸, —OCHX³⁸ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R³⁹ is independently oxo, halogen, —CX³⁹ ₃, —CHX³⁹ ₂, —CH₂X³⁹, —OCX³⁹ ₃,—OCH₂X³⁹, —OCHX³⁹ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁰-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴⁰-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R⁴⁰-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴⁰-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R⁴⁰-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R⁴⁰-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X³⁹ isindependently —F, —Cl, —Br, or —I. In embodiments, R³⁹ is independentlyoxo, halogen, —CX³⁹ ₃, —CHX³⁹ ₂, —CH₂X³⁹, —OCX³⁹ ₃, —OCH₂X³⁹, —OCHX³⁹ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴⁰ is independently oxo, halogen, —CX⁴⁰ ₃, —CHX⁴⁰ ₂, —CH₂X⁴⁰, —OCX⁴⁰ ₃,—OCH₂X⁴⁰, —OCHX⁴⁰ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X⁴⁰ is independently —F, —Cl, —Br, or —I.

In embodiments, L^(5B) is independently a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R⁴¹-substitutedor unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R⁴¹-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), R⁴¹-substitutedor unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R⁴¹-substituted or unsubstituted heterocycloalkylene(e.g., 3 to 6membered, 4 to 6 membered 4 to 5 membered, or 5 to 6 membered),R⁴¹-substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenyl), orR⁴¹-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered). In embodiments, L^(5B) isindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkylene (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted arylene (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R⁴¹ is independently oxo, halogen, —CX⁴¹ ₃, —CHX⁴¹ ₂, —CH₂X⁴¹, —OCX⁴¹ ₃,—OCH₂X⁴¹, —OCHX⁴¹ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴²-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴²-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R⁴²-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴²-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R⁴²-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R⁴²-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X⁴¹ isindependently —F, —Cl, —Br, or —I. In embodiments, R⁴¹ is independentlyoxo, halogen, —CX⁴¹ ₃, —CHX⁴¹ ₂, —CH₂X⁴¹, —OCX⁴¹ ₃, —OCH₂X⁴¹, —OCHX⁴¹ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴² is independently oxo, halogen, —CX⁴² ₃, —CHX⁴² ₂, —CH₂X⁴², —OCX⁴² ₃,—OCH₂X⁴², —OCHX⁴² ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴³-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴³-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R⁴³-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴³-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R⁴³-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R⁴³-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X⁴² isindependently —F, —Cl, —Br, or —I. In embodiments, R⁴² is independentlyoxo, halogen, —CX⁴² ₃, —CHX⁴² ₂, —CH₂X⁴², —OCX⁴² ₃, —OCH₂X⁴², —OCHX⁴² ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴³ is independently oxo, halogen, —CX⁴³ ₃, —CHX⁴³ ₂, —CH₂X⁴³, —OCX⁴³ ₃,—OCH₂X⁴³, —OCHX⁴³ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X⁴³ is independently —F, —Cl, —Br, or —I.

In embodiments, L^(5C) is independently a bond, —O—, —NH—, —C(O)—,—C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, R⁴⁴-substitutedor unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),R⁴⁴-substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, or 2 to 3 membered), R⁴⁴-substitutedor unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R⁴⁴-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R⁴⁴-substituted or unsubstituted arylene (e.g., C₆-C₁₀ or phenyl), orR⁴⁴-substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered,5 to 9 membered, or 5 to 6 membered). In embodiments, L^(5C) isindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2to 6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkylene (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted arylene (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

R⁴⁴ is independently oxo, halogen, —CX⁴⁴ ₃, —CHX⁴⁴ ₂, —CH₂X⁴⁴, —OCX⁴⁴ ₃,—OCH₂X⁴⁴, —OCHX⁴⁴ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁵-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴⁵-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R⁴⁵-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴⁵-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R⁴⁵-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R⁴⁵-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X⁴⁴ isindependently —F, —Cl, —Br, or —I. In embodiments, R⁴⁴ is independentlyoxo, halogen, —CX⁴⁴ ₃, —CHX⁴⁴ ₂, —CH₂X⁴⁴, —OCX⁴⁴ ₃, —OCH₂X⁴⁴, —OCHX⁴⁴ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴⁵ is independently oxo, halogen, —CX⁴⁵ ₃, —CHX⁴⁵ ₂, —CH₂X⁴⁵, —OCX⁴⁵ ₃,—OCH₂X⁴⁵, —OCHX⁴⁵ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, R⁴⁶-substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), R⁴⁶-substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, or2 to 3 membered), R⁴⁶-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R⁴⁶-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), R⁴⁶-substituted or unsubstituted aryl(e.g., C₆-C₁₀ or phenyl), or R⁴⁶-substituted or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). X⁴⁵ isindependently —F, —Cl, —Br, or —I. In embodiments, R⁴⁵ is independentlyoxo, halogen, —CX⁴⁵ ₃, —CHX⁴⁵ ₂, —CH₂X⁴⁵, —OCX⁴⁵ ₃, —OCH₂X⁴⁵, —OCHX⁴⁵ ₂,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, or 2 to 3 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

R⁴⁶ is independently oxo, halogen, —CX⁴⁶ ₃, —CHX⁴⁶ ₂, —CH₂X⁴⁶, —OCX⁴⁶ ₃,—OCH₂X⁴⁶, —OCHX⁴⁶ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, or 2 to 3 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). X⁴⁶ is independently —F, —Cl, —Br, or —I.

In embodiments, a compound is:

(8003).

In embodiments the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, a compound is a compound described herein, including inan aspect, embodiment, table, figure, example, scheme, or claim. Inembodiments, the compound is not bosutinib. In embodiments, the compoundis not TAK-185. In embodiments, the compound is not CP-724,714. Inembodiments, the compound is not lapatinib. In embodiments, the compoundis not neratinib.

In embodiments, a compound described herein, including adegradation-increasing moiety (e.g., R⁴ or R⁵) increases the degradationof a protein in contact with (e.g., bound to) the compound. Inembodiments, the protein contacting the compound is HER protein. Inembodiments, the protein contacting the compound is EGFR. Inembodiments, the protein contacting the compound is HER2. Inembodiments, the protein contacting the compound is HER3. Inembodiments, the protein contacting the compound is HER4. Inembodiments, a compound described herein, including adegradation-increasing moiety (e.g., R⁴ or R⁵) increases the degradationof a complex including a protein in contact with (e.g., bound to) thecompound (e.g., EGFR, HER2, HER3, or HER4). In embodiments, the complexincludes a second protein selected from EGFR, HER2, HER3, or HER4.

In embodiments, the compound is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not

In embodiments, -L⁴-R⁴ is not substituted or unsubstituted 5 to 10membered heteroalkyl. In embodiments, -L⁴-R⁴ is not substituted orunsubstituted 6 to 10 membered heteroalkyl. In embodiments, -L⁴-R⁴ isnot substituted or unsubstituted 7 to 10 membered heteroalkyl. Inembodiments, -L⁴-R⁴ is not substituted or unsubstituted 7 to 9 memberedheteroalkyl. In embodiments, -L⁴-R⁴ is not substituted or unsubstituted5 membered heteroaryl. In embodiments, -L⁴-R⁴ is not substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, -L⁴-R⁴ is notsubstituted or unsubstituted 4 to 6 membered heteroaryl. In embodiments,-L⁴-R⁴ is not substituted or unsubstituted heteroaryl. In embodiments,-L⁴-R⁴ is not substituted 5 membered heteroaryl. In embodiments, -L⁴-R⁴is not substituted 5 to 6 membered heteroaryl. In embodiments, -L⁴-R⁴ isnot substituted 4 to 6 membered heteroaryl. In embodiments, -L⁴-R⁴ isnot substituted heteroaryl. In embodiments, -L⁴-R⁴ is not unsubstituted5 membered heteroaryl. In embodiments, -L⁴-R⁴ is not unsubstituted 5 to6 membered heteroaryl. In embodiments, -L⁴-R⁴ is not unsubstitutedheteroaryl. In embodiments, -L⁴-R⁴ is not unsubstituted 4 to 6 memberedheteroaryl.

In embodiments, -L⁵-R⁵ is not

In embodiments, -L⁵-R⁵ is not substituted or unsubstituted 5 to 10membered heteroalkyl. In embodiments, -L⁵-R⁵ is not substituted orunsubstituted 6 to 10 membered heteroalkyl. In embodiments, -L⁵-R⁵ isnot substituted or unsubstituted 7 to 10 membered heteroalkyl. Inembodiments, -L⁵-R⁵ is not substituted or unsubstituted 7 to 9 memberedheteroalkyl. In embodiments, -L⁵-R⁵ is not substituted or unsubstituted5 membered heteroaryl. In embodiments, -L⁵-R⁵ is not substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, -L⁵-R⁵ is notsubstituted or unsubstituted 4 to 6 membered heteroaryl. In embodiments,-L⁵-R⁵ is not substituted or unsubstituted heteroaryl. In embodiments,-L⁵-R⁵ is not substituted 5 membered heteroaryl. In embodiments, -L⁵-R⁵is not substituted 5 to 6 membered heteroaryl. In embodiments, -L⁵-R⁵ isnot substituted 4 to 6 membered heteroaryl. In embodiments, -L⁵-R⁵ isnot substituted heteroaryl. In embodiments, -L⁵-R⁵ is not unsubstituted5 membered heteroaryl. In embodiments, -L⁵-R⁵ is not unsubstituted 5 to6 membered heteroaryl. In embodiments, -L⁵-R⁵ is not unsubstitutedheteroaryl. In embodiments, -L⁵-R⁵ is not unsubstituted 4 to 6 memberedheteroaryl.

In embodiments, -L⁵-R⁵ is not

In embodiments, -L⁵-R⁵ is not

In embodiments, -L⁵-R⁵ is not

In embodiments, -L⁵-R⁵ is not

In embodiments, -L⁵-R⁵ is not

In embodiments, -L⁵-R⁵ is not

In embodiments,

is not

in embodiments,

is not

wherein R^(1.2) and R^(1.4) are halogen, and R^(1.5) is unsubstitutedmethoxy. In embodiments, z1 is 0. In embodiments, Ring A is not arylwhen z1 is non-zero. In embodiments, Ring A is not a heteroaryl when z1is non-zero. In embodiments, Ring A is not a aryl (e.g., C₆-C₁₀ orphenyl) or 5 to 6 membered heteroaryl when z1 is non-zero. Inembodiments, Ring A is not aryl (e.g., C₆-C₁₀ or phenyl) when z1 isnon-zero. In embodiments, Ring A is not 5 to 6 membered heteroaryl whenz1 is non-zero.

In embodiments,

is not

In embodiments,

is not

In embodiments,

is not

In embodiments,

is not

when W¹ is N. In embodiments,

is not

when W¹ is C—R⁶. In embodiments,

is not

when W¹ is C(CN). In embodiments,

is not

when W¹ is N. In embodiments,

is not

when W¹ is N.

In embodiments,

is not

when W¹ is N. In embodiments,

is not

when W¹ is N. In embodiments,

is not

open W¹ is C−R⁶. In embodiments,

is not

when W¹ is C(CN). In embodiments,

is not

when W¹ is N.

In embodiments,

is not

when W¹ is N. In embodiments,

is not

when W¹ is N. In embodiments,

is not

when W¹ is C—R⁶. In embodiments,

is not

when W¹ is C(CN). In embodiments,

is not

when W¹ is N.

In embodiments, Ring B is not

In embodiments, Ring B is not

In embodiments, Ring B is not

In embodiments, Ring B is not

In embodiments, Ring B is not a substituted aryl or substitutedheteroaryl. In embodiments, Ring B is not a substituted aryl. Inembodiments, Ring B is not a substituted heteroaryl. In embodiments,Ring B is not a substituted or unsubstituted aryl (e.g., C₆-C₁₀ orphenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, Ring Bis not pyridyl when z2 is 1. In embodiments, Ring B is not pyridyl whenz2 is 2.

In embodiments, R¹ is not —Cl. In embodiments, R¹ is not halogen. Inembodiments, R¹ is not an unsubstituted methyl. In embodiments, R¹ isnot an unsubstituted C₁-C₂ alkyl. In embodiments, R¹ is not substitutedor unsubstituted C₁-C₂ alkyl. In embodiments, R¹ is not a substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). Inembodiments, R¹ is not an unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂).

In embodiments, R² is not —CF₃. In embodiments, R² is not —F. Inembodiments, R² is not halogen. In embodiments, R² is not anunsubstituted methyl. In embodiments, R² is not an unsubstituted C₁-C₂alkyl. In embodiments, R² is not substituted or unsubstituted C₁-C₂alkyl. In embodiments, R² is not a substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² is not anunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, z1 is not 1. In embodiments, z1 is not 2. Inembodiments, z1 is not 3. In embodiments, z1 is not 4. In embodiments,z1 is not 5. In embodiments, z1 is not 6. In embodiments, z1 is not 7.In embodiments, z2 is not 1. In embodiments, z2 is not 2. Inembodiments, z2 is not 3. In embodiments, z2 is not 4. In embodiments,z2 is not 5. In embodiments, z2 is not 6. In embodiments, z2 is not 7.

C. PHARMACEUTICAL COMPOSITIONS

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, as described herein, includingembodiments.

In embodiments, the pharmaceutical compositions include the activeingredient (e.g., compound described herein or pharmaceuticallyacceptable salt thereof) in a therapeutically effective amount, i.e., inan amount effective to achieve its intended purpose. The actual amounteffective for a particular application will depend, inter alia, on thecondition being treated. When administered in methods to treat adisease, such compositions will contain an amount of active ingredienteffective to achieve the desired result, e.g., inhibiting cellproliferation. In embodiments, the pharmaceutical composition includesan anti-cancer agent. In embodiments, the anti-cancer agent is an EGFRmodulator, HER2 modulator, HER4 modulator, c-MET modulator, PI3Kmodulator, MEK modulator, MAPK modulator, RAF modulator, BRAF modulator,AKT modulator, RAS modulator, KRAS modulator, heregulin modulator,neuregulin modulator, or mTOR modulator. In embodiments, the anti-canceragent is lapatinib, vemurafenib, or selumetinib,

D. METHODS OF TREATMENT

The compounds described herein are useful, inter alia, in methods oftreating cancer. Such methods include administering to a subject in needthereof an effective amount of a compound described herein, includingembodiments and pharmaceutically acceptable salts thereof. Inembodiments, the cancer is lung cancer, non-small cell lung cancer,ovarian cancer, breast cancer, triple negative breast cancer, melanoma,head and neck cancer, colon cancer, gatric cancer, glioma, orglioblastoma.

In an aspect is provided, a method of treating cancer, wherein themethod includes administering a compound described herein, or apharmaceutically acceptable salt thereof, to a subject in need thereof.In embodiments, the cancer is lung cancer, non-small cell lung cancer,ovarian cancer, breast cancer, triple negative breast cancer, melanoma,head and neck cancer, colon cancer, gatric cancer, glioma, orglioblastoma.

In another aspect a compound described herein is provided for use as amedicament.

In another aspect is provided, a method of treating a disease associatedwith HER3 activity, wherein the method includes administering a compounddescribed herein, or a pharmaceutically acceptable salt thereof, to asubject in need thereof.

In embodiments, the method includes administering a therapeuticallyeffective amount of the compound.

In embodiments, the method includes administering a second agent (e.g.,therapeutic agent). In embodiments, the second agent is an anti-canceragent. In embodiments, the anti-cancer agent is an EGFR modulator, HER2modulator, HER4 modulator, c-MET modulator, PI3K modulator, MEKmodulator, MAPK modulator, RAF modulator, BRAF modulator, AKT modulator,RAS modulator, KRAS modulator, heregulin modulator, neuregulinmodulator, or mTOR modulator. In embodiments, the anti-cancer agent islapatinib, vemurafenib, or selumetinib. In embodiments, the proteinsdescribed above are human proteins.

In an aspect is provided a method of treating a disease associated withEGFR activity, HER2 activity, HER4 activity, c-MET activity, PI3Kactivity, MEK activity, MAPK activity, RAF activity, BRAF activity, AKTactivity, RAS activity, KRAS activity, heregulin activity, or neuregulinactivity in a patient in need of such treatment, the method includingadministering a therapeutically effective amount of a compound describedherein, or a pharmaceutically acceptable salt thereof. In embodiments,the proteins described above are human proteins. In embodiments, themethod includes contacting HER3 with a compound described herein (e.g.,including a degradation-increasing moiety, for example as describedherein). In embodiments, the method includes contacting HER3 with acompound described herein (e.g., including a degradation-increasingmoiety, for example as described herein) and decreasing the level ofEGFR activity, HER2 activity, HER4 activity, c-MET activity, PI3Kactivity, MEK activity, MAPK activity, RAF activity, BRAF activity, AKTactivity, RAS activity, KRAS activity, heregulin activity, or neuregulinactivity by inhibiting the activity (e.g., binding to a second protein)of HER3 or increasing the degradation of HER3.

E. METHODS OF INHIBITING HER3

In an aspect is provided a method of inhibiting HER3 activity, themethod including contacting HER3 with an effective amount of a compounddescribed herein, or a pharmaceutically acceptable salt thereof.

In embodiments, the HER3 is a human HER3.

F. FURTHER EMBODIMENTS

Embodiment P1. A compound having the formula:

wherein Ring A is aryl or heteroaryl; Ring B is aryl or heteroaryl, W¹is N or C(R⁶); R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹,—CN, —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R² isindependently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —SO_(n2)R¹⁴,—SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹²,—N(O)_(m2), —NR¹¹R¹², —C(O)R¹³, —C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴,—NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX² ₃, —OCHX²₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R² substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ isindependently a hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —0 SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴₃, —OCHX⁴ ₂, degradation-increasing moiety, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁵ is independently a hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂,—CH₂X⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂, degradation-increasing moiety,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is independently a hydrogen,halogen, —CX⁶ ₃, —CHX⁶ ₂, —CH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶ ₃, —OCHX⁶ ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ areindependently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷and R⁸ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

L¹ is a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—,—NHC(O)NH—, —S—, substituted or unsubstituted alkylene or substituted orunsubstituted heteroalkylene; L⁴ is a bond or a divalent linker; L⁵ is abond or a divalent linker; z1 and z2 are independently an integer from 0to 7; m1, m2, v1, and v2 are independently 1 or 2; n1 and n2 areindependently an integer from 0 to 4; X¹, X², X⁴, X⁵, X⁶, and X^(A) areindependently —Cl, —Br, —I, or —F.

Embodiment P2. A compound of embodiment P1 having the formula:

wherein Ring A is phenyl or 5 or 6 membered heteroaryl; Ring B is phenylor 5 or 6 membered heteroaryl; Ring C is C₃-C₆ cycloalkyl, 3 to 6membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl; W¹ isN or C(R⁶). R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄alkyl, or 2 to 4 membered substituted or unsubstituted heteroalkyl; R²is independently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, or 2to 4 membered substituted or unsubstituted heteroalkyl; R³ isindependently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN, —SO_(n3)R¹⁸,—SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵R¹⁶,—N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸,—NR¹⁵SO₂R¹⁷, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX³ ₃, —OCHX³₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R³ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁶ isindependently a hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, substituted or unsubstituted C₁-C₄ alkyl, or 2 to 4 memberedsubstituted or unsubstituted heteroalkyl; R¹⁵, R¹⁶, R¹⁷, and R¹⁸ areindependently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁵and R¹⁶ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; L¹ is —O—, substituted orunsubstituted C₁-C₃ alkylene or substituted or unsubstituted 2 to 3membered heteroalkylene; L² is a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted C₁-C₃ alkylene or substituted or unsubstituted 2 to 3membered heteroalkylene; L⁴ is L^(4A)-L^(4B)-L^(4C) and L^(4A), L^(4B),and L^(4C) are each independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L⁵ is L^(5A)-L^(5B)-L^(5C)and L^(5A), L^(5B), and L^(5C) are each independently a bond, —O—, —NH—,—C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene; z1, z2 areindependently an integer from 0 to 4; z3 is independently an integerfrom 0 to 5; m3 and v3 are independently 1 or 2; n3 is independently aninteger from 0 to 4; X¹, X², X³, X⁴, X⁵, X⁶, and X^(A) are independently—Cl, —Br, —I, or —F.

Embodiment P3. The compound of embodiment P2, having the formula:

Embodiment P4. The compound of embodiment P3, having the formula:

wherein Y is 0 or 1.

Embodiment P5. The compound of embodiment P3, having the formula:

wherein Y is 0 or 1.

Embodiment P6. The compound of one of embodiments P1 to P5, wherein z1is 0.

Embodiment P7. The compound of one of embodiments P1 to P6, wherein z2is 0.

Embodiment P8. The compound of one of embodiments P1 to P7, wherein z3is 1.

Embodiment P9. The compound of embodiment P8, wherein R³ is —CF₃.

Embodiment P10. The compound of embodiment P8, wherein R³ is a halogen.

Embodiment P11. The compound of one of embodiments P1 to P10, wherein W¹is N.

Embodiment P12. The compound of one of embodiments P1 to P10, wherein W¹is C(R⁶).

Embodiment P13. The compound of embodiment P12, wherein R⁶ is —CN.

Embodiment P14. The compound of one of embodiments P1 to P13, wherein-L⁴-R⁴ is unsubstituted methoxy.

Embodiment P15. The compound of one of embodiments P1 to P14, wherein R⁴is a degradation-increasing moiety.

Embodiment P16. The compound of embodiment P15, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof; phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.

Embodiment P17. The compound of embodiment P16, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof.

Embodiment P18. The compound of one of embodiments P1 to P13, wherein R⁴is —NH₂.

Embodiment P19. The compound of one of embodiments P1 to P18, wherein-L⁵-R⁵ is unsubstituted methoxy.

Embodiment P20. The compound of one of embodiments P1 to P19, wherein R⁵is a degradation-increasing moiety.

Embodiment P21. The compound of embodiment P20, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof; phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.

Embodiment P22. The compound of embodiment P20, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof.

Embodiment P23. The compound of one of embodiments P1 to P18, wherein R⁵is —NH₂.

Embodiment P24. A pharmaceutical composition comprising a compound ofone of embodiments P1 to P23 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

Embodiment P25. The pharmaceutical composition of embodiment P24,further comprising an anti-cancer agent.

Embodiment P26. A method of treating a disease associated with HER3activity in a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments P1 to P23, or a pharmaceutically acceptable salt thereof.

Embodiment P27. A method of treating a disease associated with EGFRactivity, HER2 activity, HER4 activity, c-MET activity, PI3K activity,MEK activity, MAPK activity, RAF activity, BRAF activity, AKT activity,RAS activity, KRAS activity, heregulin activity, or neuregulin activityin a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments P1 to P23, or a pharmaceutically acceptable salt thereof.

Embodiment P28. A method of treating cancer in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments P1 to P23, or apharmaceutically acceptable salt thereof.

Embodiment P29. A method of inhibiting HER3 activity, said methodcomprising contacting HER3 with an effective amount of a compound of oneof embodiments P1 to P23, or a pharmaceutically acceptable salt thereof.

G. ADDITIONAL EMBODIMENTS

Embodiment 1. A compound having the formula:

wherein Ring A is aryl or heteroaryl; Ring B is aryl or heteroaryl; W¹is N or C(R⁶); R¹ is independently a halogen, —CX¹ ₂, —CHX¹ ₂, —CH₂X¹,—CN, —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R² isindependently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —SO_(n2)R¹⁴,—SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹²,—N(O)_(m2), —NR¹¹R¹², —C(O)R¹³, —C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴,——NHC═(O)NHNH¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹², —C(O)R¹³,—C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX² ₃, —OCHX² ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R² substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁴ is independently a hydrogen,halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂,degradation-increasing moiety, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ isindependently a hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵₃, —OCHX⁵ ₂, degradation-increasing moiety, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁶ is independently a hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁶ ₃, —OCHX⁶ ₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are independentlyhydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(A) ₃, —OCHX^(A) ₂, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷ andR⁸ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; L¹ is a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—,—C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted or unsubstituted alkyleneor substituted or unsubstituted heteroalkylene; L⁴ is a bond or adivalent linker; L⁵ is a bond or a divalent linker; z1 and z2 areindependently an integer from 0 to 7; m1, m2, v1, and v2 areindependently 1 or 2; n1 and n2 are independently an integer from 0 to4; X¹, X², X⁴, X⁵, X⁶, and X^(A) are independently —Cl, —Br, —I, or —F.

Embodiment 2. A compound of embodiment 1 having the formula:

wherein Ring A is phenyl or 5 or 6 membered heteroaryl; Ring B is phenylor 5 or 6 membered heteroaryl; Ring C is C₃-C₆ cycloalkyl, 3 to 6membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl; W¹ isN or C(R⁶); R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄alkyl, or 2 to 4 membered substituted or unsubstituted heteroalkyl; R²is independently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, or 2to 4 membered substituted or unsubstituted heteroalkyl; R³ isindependently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN, —SO_(n3)R¹⁸,—SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵R¹⁶,—N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸,—NR¹⁵SO₂R¹⁷, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX³ ₃, —OCHX³₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R³ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁶ isindependently a hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, substituted or unsubstituted C₁-C₄ alkyl, or 2 to 4 memberedsubstituted or unsubstituted heteroalkyl; R¹⁵, R¹⁶, R¹⁷, and R¹⁸ areindependently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁵and R¹⁶ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; L¹ is —O—, substituted orunsubstituted C₁-C₃ alkylene or substituted or unsubstituted 2 to 3membered heteroalkylene; L² is a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted C₁-C₃ alkylene or substituted or unsubstituted 2 to 3membered heteroalkylene; L⁴ is L^(4A)-L^(4B)-L^(4C) and L^(4A), L^(4B),and L^(4C) are each independently a bond —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L⁵ is L^(5A)-L^(5B)-L^(5C)and L^(5A), L^(5B), and L^(5C) are each independently a bond, —O—, —NH—,—C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene; z1, z2 areindependently an integer from 0 to 4; z3 is independently an integerfrom 0 to 5; m3 and v3 are independently 1 or 2; n3 is independently aninteger from 0 to 4; X¹, X², X³, X⁴, X⁵, X⁶, and X^(A) are independently—Cl, —Br, —I, or —F.

Embodiment 3. The compound of embodiment 2, having the formula:

Embodiment 4. The compound of embodiment 3, having the formula:

wherein Y is 0 or 1.

Embodiment 5. The compound of embodiment 3, having the formula:

wherein Y is 0 or 1.

Embodiment 6. The compound of one of embodiments 1 to 5, wherein z1 is0.

Embodiment 7. The compound of one of embodiments 1 to 6, wherein z2 is0.

Embodiment 8. The compound of one of embodiments 1to 7, wherein z3 is 1.

Embodiment 9. The compound of embodiment 8, wherein R³ is —CF₃.

Embodiment 10. The compound of embodiment 8, wherein R³ is a halogen.

Embodiment 11. The compound of one of embodiments 1 to 10, wherein W¹ isN.

Embodiment 12. The compound of one of embodiments 1 to 10, wherein W¹ isC(R⁶).

Embodiment 13. The compound of embodiment 12, wherein R⁶ is —CN.

Embodiment 14. The compound of one of embodiments 1 to 13, wherein-L⁴-R⁴ is unsubstituted methoxy.

Embodiment 15. The compound of one of embodiments 1 to 14, wherein R⁴ isa degradation-increasing moiety.

Embodiment 16. The compound of embodiment 15, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof; phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.

Embodiment 17. The compound of embodiment 16, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof.

Embodiment 18. The compound of one of embodiments 1 to 13, wherein R⁴ is—NH₂.

Embodiment 19. The compound of one of embodiments 1 to 18, wherein-L⁵-R⁵ is unsubstituted methoxy.

Embodiment 20. The compound of one of embodiments 1 to 19, wherein R⁵ isa degradation-increasing moiety.

Embodiment 21. The compound of embodiment 20, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof, phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.

Embodiment 22. The compound of embodiment 20, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof.

Embodiment 23. The compound of one of embodiments 1 to 18, wherein R⁵ is—NH₂.

Embodiment 24. A pharmaceutical composition comprising a compound of oneof embodiments 1 to 23 or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Embodiment 25. The pharmaceutical composition of embodiment 24, furthercomprising an anti-cancer agent.

Embodiment 26. A method of treating a disease associated with HER3activity in a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments 1 to 23, or a pharmaceutically acceptable salt thereof.

Embodiment 27. A method of treating a disease associated with EGFRactivity, HER2 activity, HER4 activity, c-MET activity, PI3K activity,MEK activity, MAPK activity, RAF activity, BRAF activity, AKT activity,RAS activity, KRAS activity, heregulin activity, or neuregulin activityin a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments 1 to 23, or a pharmaceutically acceptable salt thereof.

Embodiment 28. A method of treating cancer in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments 1 to 23, or apharmaceutically acceptable salt thereof.

Embodiment 29. A method of inhibiting HER3 activity, said methodcomprising contacting HER3 with an effective amount of a compound of oneof embodiments 1 to 23, or a pharmaceutically acceptable salt thereof.

Embodiment 30. A compound having the formula:

-   -   wherein    -   Ring A is aryl or heteroaryl;    -   Ring B is aryl or heteroaryl;    -   W¹ is N or C(R⁶)    -   R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,        —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,        —NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹,        —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹,        —NR⁷OR⁹, —OCHX¹ ₂, —OCHX¹ ₂, —OCH₂X¹, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; two adjacent        R¹ substituents may optionally be joined to form a substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² is independently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN,        —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹²,        —NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹²,        —C(O)R¹³, —C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴,        —NR¹¹C═(O)R¹³, —NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX² ₃, —OCHX² ₂,        —OCH₂X², substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl; two adjacent R² substituents may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R⁴ is independently a hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂,        —CH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,        —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,        —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴ ₂,        degradation-increasing moiety, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁵ is independently a hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂,        —CH₂X⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,        —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,        —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵,        degradation-increasing moiety, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R⁶ is independently a hydrogen, halogen, —CX⁶ ₃, —CHX⁶ ₂,        —CH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,        —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,        —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl    -   R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are independently        hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN, —OH,        —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,        —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,        —NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A),        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;        R⁷ and R⁸ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl; R¹¹        and R¹² substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl or substituted or unsubstituted heteroaryl;    -   L¹ is a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,        —OC(O)—, —NHC(O)NH—, —S—, substituted or unsubstituted alkylene        or substituted or unsubstituted heteroalkylene;    -   L⁴ is a bond or a divalent linker;    -   L⁵ is a bond or a divalent linker;    -   z1 and z2 are independently an integer from 0 to 7;    -   m1, m2, v1, and v2 are independently 1 or 2;    -   n1 and n2 are independently an integer from 0 to 4;    -   X¹, X², X⁴, X⁵, X⁶, and X^(A) are independently —Cl, —Br, —I, or        —F.

Embodiment 31. The compound of embodiment 30, having the formula:

Embodiment 32. A compound of embodiment 30 having the formula:

-   -   wherein    -   Ring A is phenyl or 5 or 6 membered heteroaryl;    -   Ring B is phenyl or 5 or 6 membered heteroaryl;    -   Ring C is C₃-C₆ cycloalkyl, 3 to 6 membered heterocycloalkyl,        phenyl, or 5 to 6 membered heteroaryl;    -   W¹ is N or C(R⁶);    -   R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or        unsubstituted C₁-C₄ alkyl, or 2 to 4 membered substituted or        unsubstituted heteroalkyl;    -   R² is independently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN,        —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or        unsubstituted C₁-C₄ alkyl, or 2 to 4 membered substituted or        unsubstituted heteroalkyl;    -   R³ is independently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN,        —SO_(n3)R¹⁸, —SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶,        —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵R¹⁶, —N(O)_(m3), —NR¹⁵R¹⁶,        —C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁷,        —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX³ ₃, —OCHX³ ₂,        —OCH₂X³, substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl; two adjacent R³ substituents may        optionally be joined to form a substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl,        substituted or unsubstituted aryl, or substituted or        unsubstituted heteroaryl;    -   R⁶ is independently a hydrogen, halogen, —CN, —OH, —NH₂, —COOH,        —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, or        2 to 4 membered substituted or unsubstituted heteroalkyl;    -   R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently hydrogen, halogen,        —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂,        —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,        —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(A) ₃,        —OCHX^(A) ₂, —OCH₂X^(A), substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl; R¹⁵ and R¹⁶        substituents bonded to the same nitrogen atom may optionally be        joined to form a substituted or unsubstituted heterocycloalkyl        or substituted or unsubstituted heteroaryl;    -   L¹ is —O—, substituted or unsubstituted C₁-C₃ alkylene or        substituted or unsubstituted 2 to 3 membered heteroalkylene;    -   L² is a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,        —OC(O)—, —NHC(O)NH—, —S—, substituted or unsubstituted C₁-C₃        alkylene or substituted or unsubstituted 2 to 3 membered        heteroalkylene;    -   L⁴ is L^(4A)-L^(4B)-L^(4C) and L^(4A), L^(4B), and L^(4C) are        each independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,        —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted or        unsubstituted alkylene, substituted or unsubstituted        heteroalkylene, substituted or unsubstituted cycloalkylene,        substituted or unsubstituted heterocycloalkylene, substituted or        unsubstituted arylene, or substituted or unsubstituted        heteroarylene;    -   L⁵ is L^(5A)-L^(5B)-L^(5C) and L^(5A), L^(5B), and L^(5C) are        each independently a bond, —O—, —NH—, —C(O)—, —C(O)NH—,        —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted or        unsubstituted alkylene, substituted or unsubstituted        heteroalkylene, substituted or unsubstituted cycloalkylene,        substituted or unsubstituted heterocycloalkylene, substituted or        unsubstituted arylene, or substituted or unsubstituted        heteroarylene;    -   z1, z2 are independently an integer from 0 to 4;    -   z3 is independently an integer from 0 to 5;    -   m3 and v3 are independently 1 or 2;    -   n3 is independently an integer from 0 to 4;    -   X¹, X², X³, X⁴, X⁵, X⁶, and X^(A) are independently —Cl, —Br,        —I, or —F.

Embodiment 33. The compound of embodiment 30 or embodiment 32, havingthe formula:

Embodiment 34. The compound of embodiment 32, having the formula:

wherein Y is 0 or 1.

Embodiment 35. The compound of embodiment 32, having the formula:

wherein Y is 0 or 1.

Embodiment 36. The compound of one of embodiments 30 to 35, wherein z1is 0.

Embodiment 37. The compound of one of embodiments 30 to 35, wherein z2is 0.

Embodiment 38. The compound of one of embodiments 30 to 35, wherein z3is 1.

Embodiment 39. The compound of one of embodiments 30 to 35, wherein R³is independently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCHX³ ₂,—OCH₂X³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 40. The compound of one of embodiments 30 to 35, wherein R³is independently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCX³ ₃, —OCHX³ ₂,—OCH₂X³.

Embodiment 39. The compound of one of embodiments 30 to 35, wherein R³is independently a halogen or —CF₃.

Embodiment 39. The compound of one of embodiments 30 to 35, wherein R³is independently —CF₃.

Embodiment 40. The compound of one of embodiments 30 to 35, wherein R³is a halogen.

Embodiment 41. The compound of one of embodiments 30 to 40, wherein W¹is N.

Embodiment 42. The compound of one of embodiments 30 to 40, wherein W¹is C(R⁶).

Embodiment 43. The compound of one of embodiments 30 to 42, wherein R⁶is —CN.

Embodiment 44. The compound of one of embodiments 30 to 43, wherein-L⁴-R⁴ is substituted or unsubstituted 2 to 10 membered heteroalkyl.

Embodiment 45. The compound of one of embodiments 30 to 43, wherein-L⁴-R⁴ is substituted or unsubstituted 2 to 6 membered heteroalkyl.

Embodiment 46. The compound of one of embodiments 30 to 43, wherein-L⁴-R⁴ is -L⁴-R⁴ substituted or unsubstituted 2 membered heteroalkyl.

Embodiment 47. The compound of one of embodiments 30 to 43, wherein-L⁴-R⁴ is substituted or unsubstituted methoxy.

Embodiment 48. The compound of one of embodiments 30 to 43, wherein R⁴is a degradation-increasing moiety.

Embodiment 49. The compound of one of embodiments 30 to 43, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof; phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.

Embodiment 50. The compound of embodiment 48, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof.

Embodiment 51. The compound of one of embodiments 30 to 43, wherein R⁴is hydrogen, halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂,or —OCH₂X⁴ ₂.

Embodiment 52. The compound of one of embodiments 30 to 43, wherein R⁴is hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, or—NHOH.

Embodiment 53. The compound of one of embodiments 30 to 43, wherein R⁴is —O(unsubstituted C₁-C₄ alkyl) or —NH₂.

Embodiment 54. The compound of one of embodiments 30 to 43, wherein R⁴is —O(unsubstituted C₁-C₂ alkyl) or —NH₂.

Embodiment 55. The compound of one of embodiments 30 to 43, wherein R⁴is unsubstituted methoxy or —NH₂.

Embodiment 56. The compound of one of embodiments 30 to 43, wherein R⁴is —NH₂.

Embodiment 57. The compound of one of embodiments 30 to 56, wherein-L⁵-R⁵ is substituted or unsubstituted 2 to 10 membered heteroalkyl.

Embodiment 58. The compound of one of embodiments 30 to 56, wherein-L⁵-R⁵ is substituted or unsubstituted 2 to 6 membered heteroalkyl.

Embodiment 59. The compound of one of embodiments 30 to 56, wherein-L⁵-R⁵ is -L⁵-R⁵ is substituted or unsubstituted 2 membered heteroalkyl.

Embodiment 60. The compound of one of embodiments 30 to 56, wherein-L⁵-R⁵ is substituted or unsubstituted methoxy.

Embodiment 61. The compound of one of embodiments 30 to 56, wherein R⁵is a degradation-increasing moiety.

Embodiment 62. The compound of one of embodiments 30 to 56, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof; phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.

Embodiment 63. The compound of embodiment 62, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof.

Embodiment 64. The compound of one of embodiments 30 to 56, wherein R⁵is hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂,or —OCH₂X⁵ ₂.

Embodiment 51. The compound of one of embodiments 30 to 56, wherein R⁵is hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, or—NHOH.

Embodiment 65. The compound of one of embodiments 30 to 56, wherein R⁵is —O(unsubstituted C₁-C₄ alkyl) or —NH₂.

Embodiment 66. The compound of one of embodiments 30 to 56, wherein R⁵is —O(unsubstituted C₁-C₂ alkyl) or —NH₂.

Embodiment 67. The compound of one of embodiments 30 to 56, wherein R⁵is unsubstituted methoxy or —NH₂.

Embodiment 68. The compound of one of embodiments 30 to 56, wherein R⁵is —NH₂.

H. EXAMPLES

HER3 Thermofluor Assay. Wt HER3 TKD was purified according to thepreviously published protocol¹. Thermofluor reactions were performed induplicate and set up as follows. 1 μL of an inhibitor or DMSO dilutionin 40% DMSO:water was added to 19 μL of the HER3 kinase domain inreaction buffer. The final reaction solution contained 100 mM MOPS, 200mM NaCl, 5% glycerol, 5 mM MgCl2, 0.1 mM DTT, 5× SYPRO Orange, 2 μMkinase, 2% DMSO and 20 μM inhibitor in the wells of a 96-well, lowprofile, white, PCR plate (USA scientific). The solution was pipetted upand down to mix, sealed with TempAssure clear PCR flat caps (USAScientific), centrifuged at 500×g for 30 s, and heated in a StratageneMx3005P RT-PCR machine from 25° C. to 95° C. in 0.5° C. increments every30 s after an initial incubation at 25° C. for 10 min. Fluorescence wasmeasured at the end of each 30 s period with an excitation wavelength of492 nm and an emission wavelength of 610 nm. To obtain the meltingtemperature, fluorescent signals were normalized to the maximumfluorescent signal for that well. Values after the well had reached amaximum signal were discarded and the signals were fit to the Boltzmannequation in Graphpad Prism 6. ΔT_(m) was calculated as the difference inmelting temperature between the compound-treated kinase compared to theDMSO control.

In vitro Kinase Assays. In vitro kinase assays with the HER2 kinasedomain (SignalChem) were performed in triplicate as follows. To 9 μL ofa 2.5× solution of kinase and substrate in reaction buffer was added 3μL of a 5× DMSO or inhibitor dilution in 10% DMSO:water. Theinhibitor/kinase solution was incubated at room temperature for 10minutes. The kinase assay was initiated by the addition of 3 μL of a 5×solution of ATP, and ran for 15 minutes. The final reaction conditionswere 50 mM Tris (pH7.4), 5 mM MnCl₂, 0.01% Tween-20, 2 mM DTT, 100 μME₄Y substrate (SignalChem), 15 nM HER2, 2% DMSO, 50 μM ATP, and 1 μCiγ³²P-ATP. After 15 minutes, 3 μL of each reaction was pipetted ontophosphocellulose sheets (P81, Whatman) and allowed to dry. The sheetswere then washed 4×5 min with a solution of 0.5% phosphoric acid, dried,and exposed to a phosphor screen overnight. Src Kinase assays wereconducted as previously described². Phosphorimaging was conducted on aTyphoon 9500, image intensities were quantified in ImageQuant 5.2,normalized to the DMSO control and plotted in GraphPad Prism 6.

Immunoblotting. CHLL-1 cells were grown in 6-well plates and treatedaccording to the indicated conditions at which point the media wasaspirated, cells were washed with 1 mL of cold PBS, which was thenaspirated and the plates were frozen at −80° C. The frozen cells werethawed on the plates in a buffer containing 50 mM Tris pH 7.5, 150 mMNaCl, 1 mM EDTA, and 1% Triton X-100 supplemented with 1× phosphatase(PhoSTOP, Roche) and 1× protease (complete-mini tablets, Roche)inhibitors. Lysates were scraped, transferred to Eppendorf tubes, andcleared by centrifugation at 20,000×g for 20 min at 4° C. The clarifiedlysates were transferred to chilled, clean tubes, and normalized forprotein concentration by Bradford (Bio-Rad). The normalized lysates werediluted with Laemmli loading buffer, and 10 μg of total protein was runon a 4-12% gradient gel (Invitrogen), which was then transferred to 0.45μM nitrocellulose (Bio-Rad) and analyzed using the indicated primaryantibodies according to the manufacturer's recommendations (1:1000antibody dilution). Primary antibodies were detected using IRDyesecondary antibodies (Li-Cor) according to the manufacturer'srecommendations and scanned on an Odyssey imager (Li-Cor). Scannedimages were cropped and assembled in Adobe Illustrator 6.

Chemical Synthesis

General Methods: Reactions were performed in sealed vials with magneticstirring. All commercial reagents were used without furtherpurification. Silica gel chromatography was performed on a CombiflashRf+ using column cartridges pre-packed with 40-60 micron silica(Teledyne Isco). All RP-HPLC purifications were performed with a Waters2545 binary gradient module equipped with an XBridge prep C18 columnusing H2O+0.1% formic acid and CH3CN+0.1% formic acid (5-95% gradient)while monitoring at 254 nm. Low resolution mass spectra (LC/ESI-MS) wererecorded in positive and negative mode on a Waters TQ detector with anAcquity UPLC equipped with a BUT C18 column.

6,7-dimethoxy-4-((4-phenoxyphenyl)amino)quinoline-3-carbonitrile (179D).1 was synthesized as previously reported³. 10 mg of 1 and 7.46 mg of4-phenoxyaniline was added to a vial with a magnetic stir bar. The vialwas capped, purged with argon, and 1 mL of 2-ethoxyethanol was added.The vial was heated at 150° C. for 3 h. The reaction was then cooled andpurified by RP-HPLC. Product containing fractions were pooled and driedunder reduced pressure to yield 6.4 mg (40%) of 179D as a yellow solid.MS (ES+) m/z 398.3 (M+H)⁺

4-((4-(benzyloxy)phenyl)amino-6,7-dimethoxyquinoline-3-carbonitrile(183). 183 was obtained in 61% yield as a yellow solid by a methodsimilar to the one described for compound 179D. MS (ES+) m/z 412.4(M+H)⁺

1-(3-(4-aminophenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (4). 2was synthesized as previously described⁴. 50 mg of 2 was added to a vialwith a stir bar. The vial was capped, purged with argon, and 1 mL of drydichloromethane was added. The solution was allowed to stir at 0° C. for15 minutes after which 31 μL of 3-(Trifluoromethyl)phenyl isocyanate wasadded. The reaction was stirred at 0° C. for 5 min and was then allowedto warm to 25° C. over the course of an hour. The solution was thencooled to −20° C. and filtered to yield 69.3 mg of 3 as a crude solid,which was used in the next step without further purification. 44.8 mg ofthe crude 3 was added to a vial containing 1 mL of THF and a stirbar.6.0 mg of 10% palladium on carbon was added, the vial was capped andstirred at 25° C. under a hydrogen atmosphere for 14 h. The reaction wasfiltered, concentrated in vacuo and purified by silica gelchromatography (eluent, 20% EtOAc/Hex to 100% EtOAc) to give 34.4 mg(63% over 2 steps) of 4 as a white solid. MS (ES+) m/z 388.3 (M+H)⁺¹

1-(3-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)phenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(50A). 50A was obtained in 26% yield as a yellow solid by a methodsimilar to the one described for compound 179D. MS (ES+) m/z 600.3(M+H)⁺

1-(3-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(73). 5.8 mg (0.025 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 8.5mg of 4 was added to a vial with a magnetic stir bar. The vial wascapped, purged with argon, and 1 mL of isopropanol was added. The vialwas heated at 85° C. for 1 h. The reaction was then cooled to −20° C.and the pure product was filtered off to obtain 9.3 mg (63%) of 73 as ayellow solid. MS (ES+) m/z 576.2 (M+H)⁺

N-(3-(4-nitrophenoxy)phenyl)-3-(trifluoromethyl)benzamide (6). 50 mg(0.217 mmol) of 2 was added to a vial with a stir bar. The vial wascapped, purged with argon, and 1 mL of dry dichloromethane and 0.5 mL ofdry DMF was added. The solution was allowed to stir at 0° C. for 15minutes after which 34 μL of 3-(trifluoromethyl)benzoyl chloride wasadded. The reaction was stirred at 0° C. for 5 min and was then allowedto warm to 25° C. over the course of an hour. EtOAc and water were thenadded to the reaction and the organic layer was separated. The aqueouslayer was further extracted with 2 aliquots of EtOAc. The organic layerswas pooled, washed once with water, once with brine, and reduced invacuo. The crude material was purified by column chromatography (eluentHEX to 30% EtOAc/HEX). Product containing fractions were pooled andreduced in vacuo in a vial. 10 mg of 10% palladium on carbon and 1.5 mLof THF was then added to the vial, which was capped and stirred at 25°C. under a hydrogen atmosphere for 12 h. The reaction was filtered,concentrated in vacuo and purified by silica gel chromatography (eluent,20% EtOAc/Hex to 100% EtOAc) to give 27 mg (31% over 2 steps) of 6. MS(ES+) m/z 373.2 (M+H)⁺¹

1-(3-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(74A). 74A was obtained in 85% yield as a yellow solid by a methodsimilar to the one described for compound 73. MS (ES+) m/z 561.2 (M+H)⁺

N-(3-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)phenoxy)phenyl)-3-(trifluoromethyl)benzamide(74B). 74B was obtained in 75% yield by a method similar to the onedescribed for compound 73 using 1 instead of4-chloro-6,7-dimethoxyquinazoline. MS (ES+) m/z 585.2 (M+H)⁺

1-(3-(4-aminophenoxy)phenyl)-3-phenylurea (8). 8 was obtained in 59%yield over 2 steps by a method similar to the one described for compound4. MS (ES+) m/z 320.3 (M+H)⁺

1-(3-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)phenyl)-3-phenylurea(75A). 75A was obtained in 83% yield by a method similar to the onedescribed for 73. MS (ES+) m/z 508.2 (M+H)⁺

1-(3-(4-((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)phenoxy)phenyl)-3-phenylurea(75B). 75B was obtained in 74% yield by a method similar to the onedescribed for 73 using 1 instead of 4-chloro-6,7-dimethoxyquinazoline.MS (ES+) m/z 532.2 (M+H)⁺

6-amino-4-((2,4-dichloro-5-methoxyphenyl)amino)quinoline-3-carbonitrile(11). 9 was synthesized as previously described⁵. 56.5 mg of2,4-dichloro-5-methoxyaniline was added to a vial containing 62 mg of 9and 2.5 mL of 2-ethoxyethanol. The vial was capped and heated to 145° C.for 2 h. The reaction was cooled to rt and reduced in vacuo. 2.9 mL ofMeOH, 104 mg of iron powder, and 798 μL of 3M ammonium chloride wereadded to the crude mixture containing 10, which was refluxed for 1 h at100° C. The reaction was cooled to room temperature, filtered, andreduced in vacuo. The crude material was purified by columnchromatography (eluent 50% EtOAc/HEX to 100% EtOAc). Product containingfractions were pooled and evaporated under reduced pressure yielding 28mg (29%) of 11 as a yellow solid. MS (ES+) m/z 360.64 (M+H)⁺

N-(3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)quinolin-6-yl)pent-4-ynamide(12). 5.2 mg of 4-Pentynoic acid was stirred in 2 mL of a 1:1 mixture ofTHF and DMF with 6.93 μL of isobutyl chloroformate at 0° C. under argon.5.9 μL of N-methyl morpholine was added and the solution was stirred for15 minutes. 16 mg of 11 was then added and the reaction was allowed towarm to room temperature overnight. The crude reaction was reduced invacuo and purified by RP-HPLC to yield 8.2 mg (42%) of 12 as a yellowsolid. MS (ES+) m/z 440.4 (M+H)⁺

2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)acetamide(13). 88 mg of 1-Adamantaneacetic acid, and 90 μL of11-Azido-3,6,9-trioxaundecan-1-amine was added to a vial with a stirbar. The vial was capped, purged with argon, and 2.5 mL of drydichloromethane was added 83 mg of HOBt and 237 μL of DIPEA was addedand the solution was stirred at 0° C. for 10 minutes. 104 mg of EDC wasadded and the reaction was allowed to warm to room temperatureovernight. After 12 hours, EtOAc and water were then added to thereaction and the organic layer was separated. The aqueous layer wasfurther extracted with 2 aliquots of EtOAc. The organic layer waspooled, washed once brine, dried with anhydrous MgSO4, which wasfiltered and reduced in vacuo. The crude material was purified by columnchromatography (eluent DCM to 10% MeOH/DCM). Product containingfractions were identified by CAM staining on TLC, pooled, and reduced invacuo to give 108 mg (60%) of 13 as a clear oil.

3-(1-(1-((3r,5r,7r)-adamantan-1-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)-N-(3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)quinolin-6-yl)propanamide(87). 10 mg of 12 and 9 mg of 13 were added to a vial containing 1 mL ofDMF. 22.7 μL of 1M copper sulfate and 27.3 μL of 1 M Ascorbate wereadded and the reaction was stirred at room temperature for 1 h afterwhich an additional 5.7 mL of 1M copper sulfate and 6.84 μL of 1Mascorbate was added. After 3 hours EtOAc and water were added to thereaction and the organic layer was separated. The aqueous layer wasfurther extracted with 2 aliquots of EtOAc. The organic layers werepooled, washed once brine, dried with anhydrous MgSO4, filtered, andreduced in vacuo. The crude material was purified by RP-HPLC. Productcontaining fractions were pooled and reduced in vacuo to give 8.4 mg(44%) of 87 as a yellow oil. MS (ES+) m/z 835.0 (M+H)⁺

1-(3-(4-((6-amino-3-cyanoquinolin-4-yl)amino)phenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(15). 15 was obtained in 37% yield from 9 over 2 steps by a methodsimilar to the one described for 11. MS (ES+) m/z 555.6 (M+H)⁺

8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-8-oxooctanoicacid (16). To a flame dried vial with a stir bar 25 mg of pomalidomidewas added. The vial was capped and purged with argon and 1.5 mL of dryTHF was added. While stirring at 25° C. 82 μL of Suberoyl chloride wasadded dropwise. The reaction was heated to 80° C. for 1 hour after whichthe reaction was cooled to room temperature. Water was added and thereaction was allowed to stir for 15 minutes. The mixture was thenextracted with EtOAc three times. The pooled organic layer was driedwith MgSO₄, filtered, and evaporated under reduced pressure. Thematerial was purified b column chromatography (eluent: DCM to 5%MeOH/DCM). Product containing fractions were, pooled, and reduced invacuo to give 10.7 mg (27%) of 16. MS (ES+) m/z 430.8 (M+H)⁺

N1-(3-cyano-4-((4-(3-(3-(3-(trifluoromethyl)phenyl)ureido)phenoxy)phenyl)amino)quinolin-6-yl)-N8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)octanediamide(8003) 8003 was obtained in 13% yield from 16 and 15 by a method similarto the one described for 12. MS (ES+) m/z 966.8 (M+H).

REFERENCES

1. Shi, F., Telesco, S. E., Liu, Y., Radhakrishnan, R. & Lemmon, M. A.ErbB3/HER3 intracellular domain is competent to bind ATP and catalyzeautophosphorylation. Proceedings of the National Academy of Sciences107, 7692 (2010). 2. Garske, A. L., Peters, U., Cortesi, A. T., Perez,J. L. & Shokat, K. M. Chemical genetic strategy for targeting proteinkinases based on covalent complementarity. Proceedings of the NationalAcademy of Sciences 108, 15046-15052 (2011). 3. Wissner, A. et al.4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermalgrowth factor receptor kinase and their bioisosteric relationship to the4-anilino-6,7-dialkoxyquinazoline inhibitors. Journal of MedicinalChemistry 43, 3244-3256 (2000). 4. Okaniwa. M. et al. Design andsynthesis of novel DFG-out RAF/vascular endothelial growth factorreceptor 2 (VEGFR2) inhibitors. 1. Exploration of [5,6]-fused bicyclicscaffolds. Journal of Medicinal Chemistry 55, 3452-3478 (2012). 5.Wissner, A. et al. Synthesis and structure-activity relationships of6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of anorally active, irreversible inhibitor of the tyrosine kinase activity ofthe epidermal growth factor receptor (EGFR) and the human epidermalgrowth factor receptor-2 (HER-2). Journal of Medicinal Chemistry 46,49-63 (2002).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound having the formula:

wherein Ring A is aryl or heteroaryl; Ring B is aryl or heteroaryl; W¹is C(R⁶) R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, —OCH₂X¹, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R¹ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is independently a halogen, —CX² ₃, —CHX²₂, —CH₂X², —CN, —SO_(n2)R¹⁴, —SO_(v2)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹²,—NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)_(m2), —NR¹¹R¹², —C(O)R¹³,—C(O)—OR⁹, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX² ₃, —OCHX² ₂, —OCH₂X², substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R² substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁴ is independently a hydrogen,halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴ ₂,degradation-increasing moiety, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ isindependently a hydrogen, halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵₃, —OCHX⁵ ₂, —OCH₂X⁵, degradation-increasing moiety, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁶ is independently, halogen, —CX⁶ ₃, —CHX⁶ ₂,—CH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁶ ₃, —OCHX⁶ ₂, —OCH₂X⁶, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ areindependently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A), substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁷ and R⁸ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; R¹¹ and R¹²substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl or substitutedor unsubstituted heteroaryl; L¹ is a bond, —O—, —NH—, —C(O)—, —C(O)NH—,—NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—, substituted orunsubstituted alkylene or substituted or unsubstituted heteroalkylene;L⁴ is a bond or a divalent linker; L⁵ is a bond or a divalent linker; z1and z2 are independently an integer from 0 to 7; m1, m2, v1, and v2 areindependently 1 or 2; n1 and n2 are independently an integer from 0 to4; and X¹, X², X⁴, X⁵, X⁶, and X^(A) are independently —Cl, —Br, —I, or—F.
 2. A compound of claim 1 having the formula:

wherein Ring A is phenyl or 5 or 6 membered heteroaryl; Ring B is phenylor 5 or 6 membered heteroaryl; Ring C is C₃-C₆ cycloalkyl, 3 to 6membered heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl; W¹ isC(R⁶); R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄alkyl, or 2 to 4 membered substituted or unsubstituted heteroalkyl; R²is independently a halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, or 2to 4 membered substituted or unsubstituted heteroalkyl; R³ isindependently a halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN, —SO_(n3)R¹⁸,—SO_(v3)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵R¹⁶,—N(O)_(m3), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸,—NR¹⁵SO₂R¹⁷, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX³ ₃, —OCHX³₂, —OCH₂X³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R³ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁶ is independently halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, or 2to 4 membered substituted or unsubstituted heteroalkyl; R¹⁵, R¹⁶, R¹⁷,and R¹⁸ are independently hydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂,—CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁵ and R¹⁶ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; L¹ is —O—, substituted or unsubstituted C₁-C₃ alkylene orsubstituted or unsubstituted 2 to 3 membered heteroalkylene; L² is abond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—,—NHC(O)NH—, —S—, substituted or unsubstituted C₁-C₃ alkylene orsubstituted or unsubstituted 2 to 3 membered heteroalkylene; L⁴ isL^(4A)-L^(4B)-L^(4C) and L^(4A), L^(4B), and L^(4C) are eachindependently a bond, —O—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—,—OC(O)—, —NHC(O)NH—, —S—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L⁵ is L^(5A)-L^(5B)-L^(5C)and L^(5A), L^(5B), and L^(5C) are each independently a bond, —O—, —NH—,—C(O)—, —C(O)NH—, —NHC(O)—, —C(O)O—, —OC(O)—, —NHC(O)NH—, —S—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene; z1, z2 areindependently an integer from 0 to 4; z3 is independently an integerfrom 0 to 5; m3 and v3 are independently 1 or 2; n3 is independently aninteger from 0 to 4; and X¹, X², X³, X⁴, X⁵, X⁶, and X^(A) areindependently —Cl, —Br, —I, or —F.
 3. The compound of claim 2, havingthe formula:


4. The compound of claim 3, having the formula:

wherein Y is 0 or
 1. 5. The compound of claim 3, having the formula:

wherein Y is 0 or
 1. 6. The compound of claim 1, wherein z1 and z2 are0.
 7. (canceled)
 8. (canceled)
 9. The compound of claim 2, wherein R³ is—CF₃ or halogen.
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. Thecompound of claim 1, wherein R⁶ is —CN.
 14. The compound of claim 1,wherein -L⁴-R⁴ is unsubstituted methoxy.
 15. The compound of claim 1,wherein R⁴ is a degradation-increasing moiety, wherein thedegradation-increasing moiety is thalidomide or an analog, derivative,or prodrug thereof; phthalimide or an analog, derivative, or prodrugthereof; adamantyl or an analog, derivative, or prodrug thereof; an IκBαphosphopeptide or an analog, derivative, or prodrug thereof; nutlin oran analog, derivative, or prodrug thereof; HIF-1α pentapeptide or ananalog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.
 16. (canceled) 17.(canceled)
 18. The compound of claim 1, wherein R⁴ is —NH₂.
 19. Thecompound of claim 1, wherein -L⁵-R⁵ is unsubstituted methoxy.
 20. Thecompound of claim 1, wherein R⁵ is a degradation-increasing moiety,wherein the degradation-increasing moiety is thalidomide or an analog,derivative, or prodrug thereof; phthalimide or an analog, derivative, orprodrug thereof, adamantyl or an analog, derivative, or prodrug thereof;an IκBα phosphopeptide or an analog, derivative, or prodrug thereof;nutlin or an analog, derivative, or prodrug thereof; HIF-1α pentapeptideor an analog, derivative, or prodrug thereof; or

or an analog, derivative, or prodrug thereof.
 21. (canceled) 22.(canceled)
 23. The compound of claim 1, wherein R⁵ is —NH₂.
 24. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 25. The pharmaceutical composition of claim 24,further comprising an anti-cancer agent.
 26. A method of treating adisease associated with HER3 activity in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of the compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 27. A method of treating a disease associatedwith EGFR activity, HER2 activity, HER4 activity, c-MET activity, PI3Kactivity, MEK activity, MAPK activity, RAF activity, BRAF activity, AKTactivity, RAS activity, KRAS activity, heregulin activity, or neuregulinactivity in a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 28. A method oftreating cancer in a patient in need of such treatment, said methodcomprising administering a therapeutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof. 29.A method of inhibiting HER3 activity, said method comprising contactingHER3 with an effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 30. The compound of claim 2,wherein z3 is 1.